The AKT-p21 phosphorylation signaling axis confers poor prognosis and dacarbazine resistance in melanoma

The AKT-p21 phosphorylation signaling axis confers poor prognosis and dacarbazine resistance in melanoma | 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 Article The AKT-p21 phosphorylation signaling axis confers poor prognosis and dacarbazine resistance in melanoma Gabriela Nana Colaneri, Ana Carolina Monteiro, Hátylas Azevedo, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7077835/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Dec, 2025 Read the published version in Scientific Reports → Version 1 posted 17 You are reading this latest preprint version Abstract Understanding the molecular mechanisms underlying melanoma metastasis and chemoresistance is vital to predict patients’ prognoses and develop more effective therapies. In this study, we investigated the role of p21 in melanoma progression and treatment resistance. Our findings reveal that increased gene and protein expression of p21 are strong predictors of poor prognosis in human melanoma, while reducing p21 makes these cells more responsive to chemotherapy. Immunohistochemistry experiments showed higher levels of total and cytoplasmic p21 in metastatic melanoma compared to primary melanomas and other melanocytic lesions. In silico analysis highlighted the interaction of p21 with proteins based on their location within the cell, identifying AKT1 as a potential regulator of p21. This finding corresponds with the observed positive relationship between p21 and AKT1 levels in both melanoma cell lines and patient samples. Significantly, we observed that increased p21 expression, phosphorylation and translocation to the cytoplasm are associated with resistance to the chemotherapy drug dacarbazine. Accordingly, the overexpression of p21 in a metastatic melanoma cell line led to a further increase in dacarbazine resistance, whereas downregulation of p21 sensitizes these cells to chemotherapy. In addition, both AKT downregulation and the pharmacological inhibition of PI3K diminished p21 phosphorylation, with the former intervention also sensitizing metastasis-prone cells to chemotherapy. Collectively, these findings highlight the critical role of the PI3K/AKT-p21 signaling to the regulation and subcellular localization of p21 in the context of chemotherapy resistance and melanoma prognosis. Biological sciences/Cancer Biological sciences/Cell biology Health sciences/Oncology p21 PI3K/AKT drug resistance metastasis melanoma dacarbazine Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterial.docx Suplementar20250719T141801Z1001.zip Cite Share Download PDF Status: Published Journal Publication published 29 Dec, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 18 Aug, 2025 Reviews received at journal 17 Aug, 2025 Reviews received at journal 15 Aug, 2025 Reviewers agreed at journal 11 Aug, 2025 Reviews received at journal 11 Aug, 2025 Reviewers agreed at journal 10 Aug, 2025 Reviewers agreed at journal 08 Aug, 2025 Reviewers agreed at journal 06 Aug, 2025 Reviewers agreed at journal 06 Aug, 2025 Reviewers agreed at journal 05 Aug, 2025 Reviewers agreed at journal 04 Aug, 2025 Reviewers agreed at journal 04 Aug, 2025 Reviewers invited by journal 04 Aug, 2025 Editor assigned by journal 04 Aug, 2025 Editor invited by journal 22 Jul, 2025 Submission checks completed at journal 21 Jul, 2025 First submitted to journal 21 Jul, 2025 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. 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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-7077835","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":496730155,"identity":"5f99b481-5fea-4e3a-b79d-ed89f1ff151c","order_by":0,"name":"Gabriela Nana Colaneri","email":"","orcid":"","institution":"Universidade Federal de São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Gabriela","middleName":"Nana","lastName":"Colaneri","suffix":""},{"id":496730156,"identity":"d5166104-d2f2-47fa-bf86-18290f60b8aa","order_by":1,"name":"Ana Carolina Monteiro","email":"","orcid":"","institution":"Universidade Federal de São 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