The Effect of Selinexor on Prostaglandin Synthesis in Virus-Positive Merkel Cell Carcinoma Cell Lines

The Effect of Selinexor on Prostaglandin Synthesis in Virus-Positive Merkel Cell Carcinoma Cell Lines | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Effect of Selinexor on Prostaglandin Synthesis in Virus-Positive Merkel Cell Carcinoma Cell Lines Deepika Narayanan, Brooke Bartley, Jennifer Landes, Stephen A. Moore, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4118515/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Jun, 2024 Read the published version in Archives of Dermatological Research → Version 1 posted 9 You are reading this latest preprint version Abstract Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with high rates of metastasis and mortality. In vitro studies suggest that selinexor (KPT-330), an inhibitor of exportin 1, may be a targeted therapeutic option for MCC. This selective inhibitor prevents the transport of oncogenic mRNA out of the nucleus. Of note, 80% of MCC tumors are integrated with Merkel cell polyomavirus (MCPyV), and virally encoded tumor-antigens, small T (sT) and large T (LT) mRNAs may require an exportin transporter to relocate to the cytoplasm and modulate host tumor-suppressing pathways. To explore selinexor as a targeted therapy for MCC, we examine its ability to inhibit LT and sT antigen expression in vitro and its impact on the prostaglandin synthesis pathway. Protein expression was determined through immunoblotting and quantified by densitometric analysis. Statistical significance was determined with t-test. Treatment of MCPyV-infected cell lines with selinexor resulted in a significant dose-dependent downregulation of key mediators of the prostaglandin synthesis pathway. Given the role of prostaglandin synthesis pathway in MCC, our findings suggest that selinexor, alone or in combination with immunotherapy, could be a promising treatment for MCPyV-infected MCC patients who are resistant to chemotherapy and immunotherapy. Merkel Cell Polyomavirus Merkel Cell Carcinoma Selinexor Prostaglandin Figures Figure 1 Figure 2 Figure 3 Introduction Merkel cell carcinoma (MCC) is a primary cutaneous neuroendocrine carcinoma that was named for the dense-core neuroendocrine granules and markers that are similarly found in Merkel cells [ 1 ]. The two mechanisms of MCC pathogenesis are the viral integration of Merkel cell polyomavirus (MCPyV) into the host genome and UV radiation-mediated carcinogensis [ 2 ]. UV-mediated nonviral MCC (MCCN) tumors have a predominant UV mutational signature with a very high tumor mutational burden in contrast to polyomavirus-associated MCC (MCCP) [ 2 ]. Approximately 80% of MCC tumors display clonal integration of the virus, and the virally encoded tumor antigens, small T (sT) and large T (LT), modulate host tumor-suppressor pathways [ 3 , 4 ]. Interestingly, UV-associated mutations in oncogenes and tumor suppressor genes have been found to disrupt similar pathways that are targeted by tumor antigens in MCCP [ 2 ]. MCC is commonly seen in sun-exposed extremities, head, and neck regions and typically presents as a rapidly growing, solitary red nodule. Patients affected have a median age of approximately 70 years and may be immunosuppressed [ 5 – 7 ]. Among cutaneous carcinomas, MCC is considered one of the most aggressive. At the time of diagnosis 20–25% of patients have regional lymph node metastases, 10% have satellite lesions, and approximately 5% have distant metastases. Reported 5-year survival rates range from 20.2–81.2%, depending on tumor stage and age at diagnosis [ 5 , 6 , 8 ]. For localized MCC lesions, the first-line treatment is complete surgical excision with margins ranging in size from 1–3 cm [ 9 ]. Nodal-negative cases should undergo sentinel lymph node biopsy (SLNB), while nodal-positive cases should undergo complete lymph node dissection (CLND) [ 9 ]. Radiotherapy can be used as an adjuvant therapy for localized MCC or in inoperable patients as a monotherapy [ 9 , 10 ]. Alternatively, cytotoxic chemotherapies are commonly employed for metastatic disease. Despite high initial response rate, chemotherapy is not associated with an overall survival benefit nor durable response [ 11 ]. In addition, chemotherapy is associated with high risk of toxic effects such as myelosuppression, sepsis, fatigue, alopecia, and nausea in patients aged 65 years and greater, which is the majority of the population affected by MCC [ 12 ]. Immunotherapy utilizing immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 inhibitors, is an emerging treatment for metastatic MCC. Although objective response rates show promise, the efficacy of ICIs in patients with autoimmune disorders remains less explored, primarily due to the exclusion of immunosuppressed individuals from most studies [ 9 ]. Acquired resistance can also be a concern for ICI treatment of MCC [ 13 , 14 ]. The limitations of the current treatments for local and metastatic MCC highlight a need for additional management options. Selinexor (KPT-330) is a selective inhibitor of nuclear exportin 1 (XPO1) first approved for the treatment of multiple myeloma [ 15 ]. Through inhibition of XPO1, selinexor prevents tumor suppressor mRNA and initiation factors from reaching cytoplasm for translation, resulting in cell cycle arrest and apoptosis [ 16 ]. Recently, selinexor has shown promise as a treatment for MCCP. In an in vitro study conducted in MCCP cell lines, selinexor downregulates all seven tested biomarkers associated with MCC carcinogenesis [ 17 ]. Multiple pathways have been investigated to uncover the mechanism of action underlying selinexor's effectiveness in MCC cell lines. One study showed that selinexor affects the DNA repair and synthesis pathway in MCC cell lines [ 18 ]. Application of selinexor resulted in a biologically significant downregulation of genes associated with DNA repair – ATM, ATR, CHK2, RAD51 – as well as DNA synthesis-associated gene – MLH1 [ 18 , 19 ]. Preclinical data of several types of cancer, including melanoma, demonstrates that the inhibition of the fatty acid synthesis pathway halts cancer cell proliferation and suppresses tumor growth [ 20 – 26 ]. Selinexor has also been shown to downregulate proteins involved in endogenous de novo lipogenesis in MCCP cell lines, suggesting an additional pathway by which selinexor may induce its anticancer effects [ 27 ]. Cyclooxygenase (COX)-2 overexpression and upregulation of prostaglandin synthesis have been shown to promote tumor initiation, formation, and growth through decreasing apoptosis, increasing immune evasion, and increasing sensitivity to induction of tumor formation [ 28 , 29 ]. COX-inhibitors are well-documented agents known for their ability to inhibit tumorigenesis [ 28 ]. Inhibition of COX-2 has been shown to suppress basal cell carcinoma and squamous cell carcinoma tumor development and is hypothesized to have inhibitory effects in stem-cells in melanoma [ 28 ]. Stem cells that lack COX-2 expression tend to be less aggressive and better differentiated. A study found that 77% of primary MCC tumors express COX-2 and it was related to a high mitotic rate, a characteristic of aggressive tumor behavior [ 30 ]. Material & Methods MKL-1 (Sigma-Aldrich #9111801) and MS-1 (Sigma-Aldrich #9111802) cells were grown in media containing 10% and 20% fetal bovine serum, respectively. MKL-1 and MS-1 cell lines were treated with increasing doses of selinexor for 72 hours. The control was treated with the vehicle agent ethyl alcohol. The lysates were generated using the M-PER mammalian protein extraction reagent (78503) provided by Pierce Biotechnology (Rockford, IL, USA). Lysates were loaded onto 4–12% bis-tris gels and 6% tris-glycine, and gel electrophoresis was performed using the Laemmli sodium dodecyl sulfate-polyacrylamide gel electrophoresis system and transferred to a polyvinylidene difluoride membrane. cPLA2 (cst-#5249; Cell Signaling Technology (CST), Danvers, MA, USA), COX1 (sc-70878; SCB), COX2 (cst-#12282; CST), PGD2S (sc-390717; SCB), PGE2S (sc-514224; SCB), PGF2S (#MAB7678; R&D Systems (RND), Minneapolis, MN, USA), PGI2S (#MAB7788, RND), TXA2S (PA545676, TFS), EP1 (#ab217925, Abcam, Waltham, MA, USA), EP2 (#ab167171, Abcam), EP3 (PA5-92124, TFS), EP4 (sc-55596, SCB), TBXA2R (#27159-1-AP, Proteintech, Rosemont, IL, USA), PTGFR (PA570674, TFS), PTGIR (PA5-102240, TFS), and PTGDR (#orb315671, Biorbyt, Durham, NC, USA) were used. Antibodies for glyceraldehyde 3-phosphate (GAPDH) (GT239, GeneTex, Irvine, CA, USA) were used as the loading control. Protein expression quantification was determined using chemiluminescent Western blotting, immunoblotting and densitometric analysis. Chemiluminescent detection was performed by Fluorchem E workstation (ProteinSimple Bio-techne, Inc., Minneapolis, MN, USA). Densitometric analyses of the obtained data were evaluated by AlphaView software (ProteinSimple Bio-techne Inc.). In the statistical analysis, the p-values were determined using t-test. Results Treatment of MKL-1 and MS-1 cells with selinexor resulted in significant downregulation of prostaglandin synthesis enzymes. Dose-dependent downregulation of prostaglandin synthesis enzymes after treatment with selinexor was observed by immunoblot analysis in MKL-1 (Fig. 1 a) and MS-1 (Fig. 2 a) cell lines. Densitometric analyses of the immunoblots after selinexor treatment reveal statistically significant dose-dependent reductions in prostaglandin synthesis enzyme and receptor expression in MKL-1 and MS-1 cell lines (Fig. 1 b and Fig. 2 b). Treatment with selinexor resulted in statistically significant dose-dependent reductions (p < 0.05) of cPLA2, EP3, and TBXA2R expression in MKL-1 and MS-1 cell lines. Moreover, there were highly significant reductions (p < 0.01) in the expression of COX-1, COX-2, PGE2S, TXA2S, EP4, PTGIR, and PTGDR in both cell lines. In the MKL-1 cell line specifically, statistically significant reductions were observed in PGD2S and EP2 (Fig. 1 b). Additionally, highly significant reductions were observed in PGI2S and EP1 exclusively in the MKL-1 cell line (Fig. 1 b). Discussion & Conclusions MCC is a highly aggressive primary cutaneous neuroendocrine carcinoma that typically occurs in elderly and immunocompromised individuals, often presenting in sun-exposed areas such as the extremities, head, and neck region. MCC has a recurrence rate of around 40% after definitive therapy, significantly higher than that of other skin cancers like invasive melanoma (approximately 19%), squamous cell carcinoma (approximately 5%-9%), or basal cell carcinoma (approximately 1%-2%) [ 31 ]. Tumors located in the head and neck region pose challenges for surgical treatment, while chemotherapies and immunotherapies have limitations due to toxic side effects. This underscores the importance of investigating the molecular mechanisms underlying MCC pathogenesis to identify tumor-targeted treatments directed against specific pathogenic factors. Selinexor was first proposed as a targeted MCC therapy by Gupta et al. after discovering decreased expression of XPO1, LT, and sT antigens in MCCP cell lines [ 32 ]. XPO1 is frequently overexpressed in human cancers and functions as an oncogenic driver [ 33 ]. By preventing the transport of oncogenic mRNA out of the nucleus, XPO1-inhibitors such as selinexor represent an attractive anti-cancer therapy. Further studies have uncovered selinexor’s inhibitory effects on the DNA damage response pathway, fatty acid synthesis pathway, and downregulation of critical biomarkers of MCC carcinogenesis [ 18 , 17 , 27 ]. The prostaglandin synthesis pathway investigated in this study represents a promising avenue for targeted MCC therapy. COX-2 expression is detected in 77% of primary MCC tumors, and its well-documented overexpression has been shown to promote tumorigenesis [ 28 , 30 ]. Both COX-1 and COX-2 enzymes are responsible for converting arachidonic acids into prostaglandin H2 (PGH2), which serves as a precursor for various prostaglandins (PGD2, PGE2, PGF2, PGI2) and thromboxane A2 (TXA2) (Fig. 3 ). TXA2 binds to its downstream receptor TXA2R. PGE2 binds to downstream E prostanoid (EP) receptors (EP1, EP2, EP3, EP4), while PGD2, PGF2, and PGI2 bind to their respective downstream receptors (PTGDR, PTGFR, PTGIR). Overexpression of EP receptors has been linked to tumor growth promotion, tumor-associated angiogenesis, regulation of cellular migration, and has been identified in various malignancies [ 29 , 34 , 35 , 36 , 37 , 38 ]. Notably, EP-receptor targeted therapies are being investigated for colorectal and breast cancer [ 39 , 40 ]. Our study demonstrates that selinexor treatment of MCCP cell lines results in highly significant dose-dependent reductions in the expression of COX enzymes, prostaglandin synthases (PGE2S), and downstream receptors (EP, PTGIR, PTGDR) in vitro . These findings underscore the potential of selinexor as a promising therapeutic agent. Furthermore, our study provides insights into yet other mechanisms by which selinexor may inhibit carcinogenic pathways, potentially by inhibiting exportin transporters and impeding the relocation of MCPyV virally encoded tumor antigens to the cytoplasm, thus curtailing the dysregulation of downstream pathways. Selinexor exhibits a dose-dependent reduction of key mediators in the prostaglandin synthesis pathway in MCCP cell lines. This pathway has been implicated in carcinogenesis and found to be dysregulated in primary MCC tumors. Our findings provide further insights into the mechanism of action and efficacy of selinexor in vitro , suggesting its potential involvement in inhibiting the prostaglandin synthesis pathway in cancer cells. Further studies are needed to investigate whether MCCN displays a similar prostaglandin pathway dysregulation, and if selinexor maintains its effect in MCCN. Selinexor is used in the second-line setting for patients with multiple myeloma [ 15 ]. Frequently reported adverse effects include gastrointestinal, constitutional, and hematologic (thrombocytopenia and neutropenia). These adverse effects are reversible and can be managed with supportive care. Importantly, no reports or evidence of major organ or cumulative toxicities after long-term treatment have been found [ 41 , 42 ]. The low side-effect profile coupled with our studies may allow for expanded indications of selinexor for MCC. Selinexor offers a promising novel therapeutic option for patients with aggressive metastatic MCC who demonstrate inadequate response to chemotherapy and immunotherapy or experience significant toxic side effects. It may be used as a standalone treatment or in combination with existing treatment options. Additional research and clinical studies are necessary to assess the impact of selinexor through in vivo experiments and its efficacy in patients with MCC. Moreover, our findings prompt the exploration of the potential therapeutic role of COX-inhibitors in the treatment of MCC. Declarations Funding source: None Conflict of Interest: The authors declare that they have no conflict of interest. Acknowledgements: None Author Contributions: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Deepika Narayanan, Brooke Bartley, Jennifer Landes, Stephen Moore, Veda Kulkarni, Qin He, and Rebecca Simonette. The first draft of the manuscript was written by Deepika Narayanan and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. References Tang CK, Toker C. Trabecular carcinoma of the skin. An ultrastructural study. Cancer . 1978;42(5):2311-2321. https://doi.org/10.1002/1097-0142(197811)42:53.0.CO;2-L DeCaprio JA. Molecular pathogenesis of merkel cell carcinoma. 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Cite Share Download PDF Status: Published Journal Publication published 01 Jun, 2024 Read the published version in Archives of Dermatological Research → Version 1 posted Editorial decision: Accepted 26 Apr, 2024 Reviews received at journal 26 Apr, 2024 Reviewers agreed at journal 26 Apr, 2024 Reviewers agreed at journal 23 Apr, 2024 Reviewers agreed at journal 29 Mar, 2024 Reviewers invited by journal 27 Mar, 2024 Submission checks completed at journal 18 Mar, 2024 Editor assigned by journal 18 Mar, 2024 First submitted to journal 17 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4118515","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":283986896,"identity":"56b5dad3-5747-4369-a8e1-f668c1eb7b91","order_by":0,"name":"Deepika Narayanan","email":"","orcid":"","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":false,"prefix":"","firstName":"Deepika","middleName":"","lastName":"Narayanan","suffix":""},{"id":283986897,"identity":"db24ece8-a4ab-45f6-a530-4b89850b5859","order_by":1,"name":"Brooke Bartley","email":"","orcid":"","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":false,"prefix":"","firstName":"Brooke","middleName":"","lastName":"Bartley","suffix":""},{"id":283986898,"identity":"696c3d0f-59d7-452b-b198-abd3a2365d52","order_by":2,"name":"Jennifer Landes","email":"","orcid":"","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"","lastName":"Landes","suffix":""},{"id":283986899,"identity":"82aef374-f939-4bbb-8d55-5d5827e8f154","order_by":3,"name":"Stephen A. Moore","email":"","orcid":"","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":false,"prefix":"","firstName":"Stephen","middleName":"A.","lastName":"Moore","suffix":""},{"id":283986900,"identity":"0e48799c-c21f-41d1-99d1-46242f4c778f","order_by":4,"name":"Veda Kulkarni","email":"","orcid":"","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":false,"prefix":"","firstName":"Veda","middleName":"","lastName":"Kulkarni","suffix":""},{"id":283986901,"identity":"ba94e69d-b1b3-4250-baab-88b919fe7601","order_by":5,"name":"Qin He","email":"","orcid":"","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":false,"prefix":"","firstName":"Qin","middleName":"","lastName":"He","suffix":""},{"id":283986902,"identity":"118bafbe-b44c-4384-a7e6-b486c590827b","order_by":6,"name":"Rebecca Simonette","email":"","orcid":"","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":false,"prefix":"","firstName":"Rebecca","middleName":"","lastName":"Simonette","suffix":""},{"id":283986903,"identity":"b0f58bb7-7f44-4dc2-ac32-e30efc84d039","order_by":7,"name":"Hung Q. Doan","email":"","orcid":"","institution":"The University of Texas MD Anderson Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Hung","middleName":"Q.","lastName":"Doan","suffix":""},{"id":283986904,"identity":"007441d2-6df0-4ccc-a32b-075920af165e","order_by":8,"name":"Peter L. Rady","email":"","orcid":"","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"L.","lastName":"Rady","suffix":""},{"id":283986905,"identity":"a38fc0c0-9628-44a9-bfe9-2621198bfa95","order_by":9,"name":"Stephen K. Tyring","email":"data:image/png;base64,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","orcid":"","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":true,"prefix":"","firstName":"Stephen","middleName":"K.","lastName":"Tyring","suffix":""}],"badges":[],"createdAt":"2024-03-17 19:59:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4118515/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4118515/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00403-024-03108-8","type":"published","date":"2024-06-01T11:41:35+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":53663704,"identity":"a6596491-199e-4918-ab25-b2034a222f93","added_by":"auto","created_at":"2024-03-28 16:32:11","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":289491,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea)\u003c/strong\u003e Expression of prostaglandin pathway synthesis enzymes and receptors in MKL-1 cell lines. Column C in both immunoblots represents the vehicle control. The immunoblots depict MKL-1 cells treated with 5, 7.5, 10, and 15 nmol L\u003csup\u003e-1\u003c/sup\u003e selinexor in each successive lane. Antibodies against prostaglandin synthesis pathway enzymes and receptors were used, with glyceraldehyde 3-phosphate (GAPDH) utilized as the loading control. Western immunoblotting represents three experiments and exhibits changes in protein expression following selinexor treatment. \u003cstrong\u003e1b)\u003c/strong\u003e Effect of selinexor on the expression of prostaglandin pathway synthesis enzymes and receptors in MKL-1 cells. The columns represent results of three target protein/GAPDH ratios from densitometric measurements of three experiments.\u0026nbsp; The densitometric analysis illustrates the dose-dependent reductions of each protein assessed as a percentage of the control. Statistically significant p-values are indicated by * (p \u0026lt; 0.05). Highly statistically significant p-values are indicated by ** (p \u0026lt; 0.01)\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4118515/v1/4c3976e77fbbd7f2d367fb5b.jpg"},{"id":53662891,"identity":"4f4d60dd-b16f-4d2d-913b-17c9f865b2cd","added_by":"auto","created_at":"2024-03-28 16:24:11","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":290424,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea)\u003c/strong\u003e Expression of prostaglandin pathway synthesis enzymes and receptors in MS-1 cell lines. Column C in both immunoblots represents the vehicle control. The immunoblots depict MS-1 cells treated with 25, 100, 500, and 750 nmol L\u003csup\u003e-1\u003c/sup\u003e selinexor in each successive lane. Antibodies against prostaglandin synthesis pathway enzymes and receptors were used, with glyceraldehyde 3-phosphate (GAPDH) utilized as the loading control. Western immunoblotting represents three experiments and exhibits changes in protein expression following selinexor treatment. \u003cstrong\u003e2b)\u003c/strong\u003e Effect of selinexor on the expression of prostaglandin synthesis enzymes and receptors in MS-1 cells. The columns represent results of three target protein/GAPDH ratios from densitometric measurements of three experiments.\u0026nbsp; The densitometric analysis illustrates the dose-dependent reductions of each protein assessed as a percentage of the control. Statistically significant p-values are indicated by * (p \u0026lt; 0.05). Highly statistically significant p-values are indicated by ** (p \u0026lt; 0.01)\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4118515/v1/04b9ec2382ddce00e09b3fb7.jpg"},{"id":53662893,"identity":"490e27d2-a2f8-49e6-b6d5-fd49ccd77c1e","added_by":"auto","created_at":"2024-03-28 16:24:11","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":159314,"visible":true,"origin":"","legend":"\u003cp\u003eThe prostaglandin synthesis pathway is responsible for converting arachidonic acid to prostaglandins and other lipids. Abbreviations: cyclooxygenase (COX), cytosolic phospholipase A2 (cPLA2), prostaglandin (PG), 2 synthase (2S), prostaglandin receptor (PTG R), Thromboxane-A (TXA), E prostanoid (EP)\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4118515/v1/9fa99b571ac8f8c0418b73e1.jpg"},{"id":59104107,"identity":"23ffd1a7-c8cb-4142-a067-e1dabeb27ee3","added_by":"auto","created_at":"2024-06-26 11:41:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1068031,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4118515/v1/a80ebfd2-aef8-445b-925a-a81e7549d68e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Effect of Selinexor on Prostaglandin Synthesis in Virus-Positive Merkel Cell Carcinoma Cell Lines","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMerkel cell carcinoma (MCC) is a primary cutaneous neuroendocrine carcinoma that was named for the dense-core neuroendocrine granules and markers that are similarly found in Merkel cells [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The two mechanisms of MCC pathogenesis are the viral integration of Merkel cell polyomavirus (MCPyV) into the host genome and UV radiation-mediated carcinogensis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. UV-mediated nonviral MCC (MCCN) tumors have a predominant UV mutational signature with a very high tumor mutational burden in contrast to polyomavirus-associated MCC (MCCP) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Approximately 80% of MCC tumors display clonal integration of the virus, and the virally encoded tumor antigens, small T (sT) and large T (LT), modulate host tumor-suppressor pathways [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Interestingly, UV-associated mutations in oncogenes and tumor suppressor genes have been found to disrupt similar pathways that are targeted by tumor antigens in MCCP [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMCC is commonly seen in sun-exposed extremities, head, and neck regions and typically presents as a rapidly growing, solitary red nodule. Patients affected have a median age of approximately 70 years and may be immunosuppressed [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Among cutaneous carcinomas, MCC is considered one of the most aggressive. At the time of diagnosis 20\u0026ndash;25% of patients have regional lymph node metastases, 10% have satellite lesions, and approximately 5% have distant metastases. Reported 5-year survival rates range from 20.2\u0026ndash;81.2%, depending on tumor stage and age at diagnosis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFor localized MCC lesions, the first-line treatment is complete surgical excision with margins ranging in size from 1\u0026ndash;3 cm [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Nodal-negative cases should undergo sentinel lymph node biopsy (SLNB), while nodal-positive cases should undergo complete lymph node dissection (CLND) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Radiotherapy can be used as an adjuvant therapy for localized MCC or in inoperable patients as a monotherapy [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Alternatively, cytotoxic chemotherapies are commonly employed for metastatic disease. Despite high initial response rate, chemotherapy is not associated with an overall survival benefit nor durable response [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In addition, chemotherapy is associated with high risk of toxic effects such as myelosuppression, sepsis, fatigue, alopecia, and nausea in patients aged 65 years and greater, which is the majority of the population affected by MCC [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Immunotherapy utilizing immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 inhibitors, is an emerging treatment for metastatic MCC. Although objective response rates show promise, the efficacy of ICIs in patients with autoimmune disorders remains less explored, primarily due to the exclusion of immunosuppressed individuals from most studies [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Acquired resistance can also be a concern for ICI treatment of MCC [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The limitations of the current treatments for local and metastatic MCC highlight a need for additional management options.\u003c/p\u003e \u003cp\u003eSelinexor (KPT-330) is a selective inhibitor of nuclear exportin 1 (XPO1) first approved for the treatment of multiple myeloma [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Through inhibition of XPO1, selinexor prevents tumor suppressor mRNA and initiation factors from reaching cytoplasm for translation, resulting in cell cycle arrest and apoptosis [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Recently, selinexor has shown promise as a treatment for MCCP. In an \u003cem\u003ein vitro\u003c/em\u003e study conducted in MCCP cell lines, selinexor downregulates all seven tested biomarkers associated with MCC carcinogenesis [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMultiple pathways have been investigated to uncover the mechanism of action underlying selinexor's effectiveness in MCC cell lines. One study showed that selinexor affects the DNA repair and synthesis pathway in MCC cell lines [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Application of selinexor resulted in a biologically significant downregulation of genes associated with DNA repair \u0026ndash; \u003cem\u003eATM, ATR, CHK2, RAD51\u003c/em\u003e \u0026ndash; as well as DNA synthesis-associated gene \u0026ndash; \u003cem\u003eMLH1\u003c/em\u003e [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Preclinical data of several types of cancer, including melanoma, demonstrates that the inhibition of the fatty acid synthesis pathway halts cancer cell proliferation and suppresses tumor growth [\u003cspan additionalcitationids=\"CR21 CR22 CR23 CR24 CR25\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Selinexor has also been shown to downregulate proteins involved in endogenous \u003cem\u003ede novo\u003c/em\u003e lipogenesis in MCCP cell lines, suggesting an additional pathway by which selinexor may induce its anticancer effects [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCyclooxygenase (COX)-2 overexpression and upregulation of prostaglandin synthesis have been shown to promote tumor initiation, formation, and growth through decreasing apoptosis, increasing immune evasion, and increasing sensitivity to induction of tumor formation [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. COX-inhibitors are well-documented agents known for their ability to inhibit tumorigenesis [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Inhibition of COX-2 has been shown to suppress basal cell carcinoma and squamous cell carcinoma tumor development and is hypothesized to have inhibitory effects in stem-cells in melanoma [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Stem cells that lack COX-2 expression tend to be less aggressive and better differentiated. A study found that 77% of primary MCC tumors express COX-2 and it was related to a high mitotic rate, a characteristic of aggressive tumor behavior [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e"},{"header":"Material \u0026 Methods","content":"\u003cp\u003eMKL-1 (Sigma-Aldrich #9111801) and MS-1 (Sigma-Aldrich #9111802) cells were grown in media containing 10% and 20% fetal bovine serum, respectively. MKL-1 and MS-1 cell lines were treated with increasing doses of selinexor for 72 hours. The control was treated with the vehicle agent ethyl alcohol. The lysates were generated using the M-PER mammalian protein extraction reagent (78503) provided by Pierce Biotechnology (Rockford, IL, USA). Lysates were loaded onto 4\u0026ndash;12% bis-tris gels and 6% tris-glycine, and gel electrophoresis was performed using the Laemmli sodium dodecyl sulfate-polyacrylamide gel electrophoresis system and transferred to a polyvinylidene difluoride membrane. cPLA2 (cst-#5249; Cell Signaling Technology (CST), Danvers, MA, USA), COX1 (sc-70878; SCB), COX2 (cst-#12282; CST), PGD2S (sc-390717; SCB), PGE2S (sc-514224; SCB), PGF2S (#MAB7678; R\u0026amp;D Systems (RND), Minneapolis, MN, USA), PGI2S (#MAB7788, RND), TXA2S (PA545676, TFS), EP1 (#ab217925, Abcam, Waltham, MA, USA), EP2 (#ab167171, Abcam), EP3 (PA5-92124, TFS), EP4 (sc-55596, SCB), TBXA2R (#27159-1-AP, Proteintech, Rosemont, IL, USA), PTGFR (PA570674, TFS), PTGIR (PA5-102240, TFS), and PTGDR (#orb315671, Biorbyt, Durham, NC, USA) were used. Antibodies for glyceraldehyde 3-phosphate (GAPDH) (GT239, GeneTex, Irvine, CA, USA) were used as the loading control.\u003c/p\u003e \u003cp\u003eProtein expression quantification was determined using chemiluminescent Western blotting, immunoblotting and densitometric analysis. Chemiluminescent detection was performed by Fluorchem E workstation (ProteinSimple Bio-techne, Inc., Minneapolis, MN, USA). Densitometric analyses of the obtained data were evaluated by AlphaView software (ProteinSimple Bio-techne Inc.). In the statistical analysis, the p-values were determined using t-test.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eTreatment of MKL-1 and MS-1 cells with selinexor resulted in significant downregulation of prostaglandin synthesis enzymes. Dose-dependent downregulation of prostaglandin synthesis enzymes after treatment with selinexor was observed by immunoblot analysis in MKL-1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea) and MS-1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea) cell lines. Densitometric analyses of the immunoblots after selinexor treatment reveal statistically significant dose-dependent reductions in prostaglandin synthesis enzyme and receptor expression in MKL-1 and MS-1 cell lines (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). Treatment with selinexor resulted in statistically significant dose-dependent reductions (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) of cPLA2, EP3, and TBXA2R expression in MKL-1 and MS-1 cell lines. Moreover, there were highly significant reductions (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) in the expression of COX-1, COX-2, PGE2S, TXA2S, EP4, PTGIR, and PTGDR in both cell lines. In the MKL-1 cell line specifically, statistically significant reductions were observed in PGD2S and EP2 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). Additionally, highly significant reductions were observed in PGI2S and EP1 exclusively in the MKL-1 cell line (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion \u0026 Conclusions","content":"\u003cp\u003eMCC is a highly aggressive primary cutaneous neuroendocrine carcinoma that typically occurs in elderly and immunocompromised individuals, often presenting in sun-exposed areas such as the extremities, head, and neck region. MCC has a recurrence rate of around 40% after definitive therapy, significantly higher than that of other skin cancers like invasive melanoma (approximately 19%), squamous cell carcinoma (approximately 5%-9%), or basal cell carcinoma (approximately 1%-2%) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Tumors located in the head and neck region pose challenges for surgical treatment, while chemotherapies and immunotherapies have limitations due to toxic side effects. This underscores the importance of investigating the molecular mechanisms underlying MCC pathogenesis to identify tumor-targeted treatments directed against specific pathogenic factors.\u003c/p\u003e \u003cp\u003eSelinexor was first proposed as a targeted MCC therapy by Gupta et al. after discovering decreased expression of XPO1, LT, and sT antigens in MCCP cell lines [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. XPO1 is frequently overexpressed in human cancers and functions as an oncogenic driver [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. By preventing the transport of oncogenic mRNA out of the nucleus, XPO1-inhibitors such as selinexor represent an attractive anti-cancer therapy. Further studies have uncovered selinexor\u0026rsquo;s inhibitory effects on the DNA damage response pathway, fatty acid synthesis pathway, and downregulation of critical biomarkers of MCC carcinogenesis [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe prostaglandin synthesis pathway investigated in this study represents a promising avenue for targeted MCC therapy. COX-2 expression is detected in 77% of primary MCC tumors, and its well-documented overexpression has been shown to promote tumorigenesis [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Both COX-1 and COX-2 enzymes are responsible for converting arachidonic acids into prostaglandin H2 (PGH2), which serves as a precursor for various prostaglandins (PGD2, PGE2, PGF2, PGI2) and thromboxane A2 (TXA2) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). TXA2 binds to its downstream receptor TXA2R. PGE2 binds to downstream E prostanoid (EP) receptors (EP1, EP2, EP3, EP4), while PGD2, PGF2, and PGI2 bind to their respective downstream receptors (PTGDR, PTGFR, PTGIR). Overexpression of EP receptors has been linked to tumor growth promotion, tumor-associated angiogenesis, regulation of cellular migration, and has been identified in various malignancies [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Notably, EP-receptor targeted therapies are being investigated for colorectal and breast cancer [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOur study demonstrates that selinexor treatment of MCCP cell lines results in highly significant dose-dependent reductions in the expression of COX enzymes, prostaglandin synthases (PGE2S), and downstream receptors (EP, PTGIR, PTGDR) \u003cem\u003ein vitro\u003c/em\u003e. These findings underscore the potential of selinexor as a promising therapeutic agent. Furthermore, our study provides insights into yet other mechanisms by which selinexor may inhibit carcinogenic pathways, potentially by inhibiting exportin transporters and impeding the relocation of MCPyV virally encoded tumor antigens to the cytoplasm, thus curtailing the dysregulation of downstream pathways.\u003c/p\u003e \u003cp\u003eSelinexor exhibits a dose-dependent reduction of key mediators in the prostaglandin synthesis pathway in MCCP cell lines. This pathway has been implicated in carcinogenesis and found to be dysregulated in primary MCC tumors. Our findings provide further insights into the mechanism of action and efficacy of selinexor \u003cem\u003ein vitro\u003c/em\u003e, suggesting its potential involvement in inhibiting the prostaglandin synthesis pathway in cancer cells. Further studies are needed to investigate whether MCCN displays a similar prostaglandin pathway dysregulation, and if selinexor maintains its effect in MCCN.\u003c/p\u003e \u003cp\u003eSelinexor is used in the second-line setting for patients with multiple myeloma [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Frequently reported adverse effects include gastrointestinal, constitutional, and hematologic (thrombocytopenia and neutropenia). These adverse effects are reversible and can be managed with supportive care. Importantly, no reports or evidence of major organ or cumulative toxicities after long-term treatment have been found [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. The low side-effect profile coupled with our studies may allow for expanded indications of selinexor for MCC.\u003c/p\u003e \u003cp\u003eSelinexor offers a promising novel therapeutic option for patients with aggressive metastatic MCC who demonstrate inadequate response to chemotherapy and immunotherapy or experience significant toxic side effects. It may be used as a standalone treatment or in combination with existing treatment options. Additional research and clinical studies are necessary to assess the impact of selinexor through \u003cem\u003ein vivo\u003c/em\u003e experiments and its efficacy in patients with MCC. Moreover, our findings prompt the exploration of the potential therapeutic role of COX-inhibitors in the treatment of MCC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding source:\u003c/strong\u003e None\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements: None\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Deepika Narayanan, Brooke Bartley, Jennifer Landes, Stephen Moore, Veda Kulkarni, Qin He, and Rebecca Simonette. The first draft of the manuscript was written by Deepika Narayanan and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTang CK, Toker C. Trabecular carcinoma of the skin. An ultrastructural study. \u003cem\u003eCancer\u003c/em\u003e. 1978;42(5):2311-2321. https://doi.org/10.1002/1097-0142(197811)42:5\u0026lt;2311::AID-CNCR2820420531\u0026gt;3.0.CO;2-L\u003c/li\u003e\n\u003cli\u003eDeCaprio JA. Molecular pathogenesis of merkel cell carcinoma. \u003cem\u003eAnnu Rev Pathol\u003c/em\u003e. 2021; 16: 69\u0026ndash; 91. https://doi.org/10.1146/annurev-pathmechdis-012419-032817\u003c/li\u003e\n\u003cli\u003eFeng H, Shuda M, Chang Y, et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. \u003cem\u003eScience\u003c/em\u003e. 2008; 319: 1096\u0026ndash;100. https://doi.org/10.1126/science.1152586\u003c/li\u003e\n\u003cli\u003eHouben R, Shuda M, Weinkam R, et al. 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The \u0026apos;comeback\u0026apos; of Selinexor: From toxic to tolerable. \u003cem\u003eCurr Probl Cancer.\u003c/em\u003e 2022 Feb;46(1):100789. https://doi.org/10.1016/j.currproblcancer.2021.100789\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"archives-of-dermatological-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Archives of Dermatological Research](https://www.springer.com/journal/403)","snPcode":"403","submissionUrl":"https://submission.nature.com/new-submission/403/3","title":"Archives of Dermatological Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Merkel Cell Polyomavirus, Merkel Cell Carcinoma, Selinexor, Prostaglandin","lastPublishedDoi":"10.21203/rs.3.rs-4118515/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4118515/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMerkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with high rates of metastasis and mortality. \u003cem\u003eIn vitro\u003c/em\u003e studies suggest that selinexor (KPT-330), an inhibitor of exportin 1, may be a targeted therapeutic option for MCC. This selective inhibitor prevents the transport of oncogenic mRNA out of the nucleus. Of note, 80% of MCC tumors are integrated with Merkel cell polyomavirus (MCPyV), and virally encoded tumor-antigens, small T (sT) and large T (LT) mRNAs may require an exportin transporter to relocate to the cytoplasm and modulate host tumor-suppressing pathways.\u003c/p\u003e \u003cp\u003eTo explore selinexor as a targeted therapy for MCC, we examine its ability to inhibit LT and sT antigen expression \u003cem\u003ein vitro\u003c/em\u003e and its impact on the prostaglandin synthesis pathway.\u003c/p\u003e \u003cp\u003eProtein expression was determined through immunoblotting and quantified by densitometric analysis. Statistical significance was determined with t-test.\u003c/p\u003e \u003cp\u003eTreatment of MCPyV-infected cell lines with selinexor resulted in a significant dose-dependent downregulation of key mediators of the prostaglandin synthesis pathway. Given the role of prostaglandin synthesis pathway in MCC, our findings suggest that selinexor, alone or in combination with immunotherapy, could be a promising treatment for MCPyV-infected MCC patients who are resistant to chemotherapy and immunotherapy.\u003c/p\u003e","manuscriptTitle":"The Effect of Selinexor on Prostaglandin Synthesis in Virus-Positive Merkel Cell Carcinoma Cell Lines","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-28 16:24:06","doi":"10.21203/rs.3.rs-4118515/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2024-04-26T20:29:49+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-26T20:07:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"194417887403788264998829810554853868323","date":"2024-04-26T20:06:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"dcdc4e21-661c-4440-a815-20cf063c98cf","date":"2024-04-23T15:59:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"d7af1f53-d9ae-4cdf-8e1b-d6a05ea95197","date":"2024-03-30T03:36:42+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-27T22:25:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-18T09:06:56+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-18T09:06:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"Archives of Dermatological Research","date":"2024-03-17T19:52:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"archives-of-dermatological-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Archives of Dermatological Research](https://www.springer.com/journal/403)","snPcode":"403","submissionUrl":"https://submission.nature.com/new-submission/403/3","title":"Archives of Dermatological Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e4e8a21c-7068-4e6e-8cb4-262e5dbae66c","owner":[],"postedDate":"March 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-06-26T11:41:35+00:00","versionOfRecord":{"articleIdentity":"rs-4118515","link":"https://doi.org/10.1007/s00403-024-03108-8","journal":{"identity":"archives-of-dermatological-research","isVorOnly":false,"title":"Archives of Dermatological Research"},"publishedOn":"2024-06-01 11:41:35","publishedOnDateReadable":"June 1st, 2024"},"versionCreatedAt":"2024-03-28 16:24:06","video":"","vorDoi":"10.1007/s00403-024-03108-8","vorDoiUrl":"https://doi.org/10.1007/s00403-024-03108-8","workflowStages":[]},"version":"v1","identity":"rs-4118515","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4118515","identity":"rs-4118515","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}