The possible role furin and furin inhibitors in endometrial adenocarcinoma: A narrative review.

Expression and activity of furin are essential for tumor progression and metastasis via activation of MMPs, which are correlated with tumor aggressiveness. 100 Furin inhibitors could be of therapeutic value in inflammation, infection, and cancer. 101 It has been reported that polyarginines are potent furin inhibitors. 101 Small molecule compounds that inhibit furin and/or furin are of great value in cancer management. 100 In vitro and vivo findings showed that furin inhibitor alpha‐1PDX reduced tumorigenicity in a considerable way. 100 Despite evidence of efficacy in preclinical studies, no furin inhibitor is used clinically. Therefore, repurposing clinically FDA‐approved furin inhibitors is of great value. Insulin‐sensitizing drug metformin had been confirmed by preclinical in vitro study to inhibit furin and other genes associated with tumor progression and invasion. 102 Of interest, in vitro invasion in EAC was considerably inhibited by sera from women with polycystic ovarian syndrome following 6 months of metformin treatment. 103 This effect is mediated by the inhibition of MMP‐2/9 and furin. 103 Other studies also confirmed the effectiveness of metformin against EAC. 104 , 105 , 106 , 107 In addition, metformin reverses obesity‐induced aggressiveness of EAC by inhibiting growth factors. 108 It has been shown that metformin the proliferation of EAC as documented in an in vitro study in a dose‐dependent manner in progesterone resistance Ishikawa cells by inducing autophagy 108 signifying that metformin is effective in progesterone resistance EAC. A randomized clinical trial started in 2019, showed that medroxyprogesterone acetate in combination with metformin is an effective therapeutic strategy against EAC. 105 A systematic review and meta‐analysis showed that metformin in combination with progestin is more effective than progestin alone in the management of atypical endometrial hyperplasia and early EAC. 109 Metformin can mitigate abnormal glucose metabolism, IR, and hyperinsulinemia, which are involved in the pathogenesis of EAC. 105 In addition, medroxyprogesterone antagonizes the carcinogenic effect of estrogen, 105 therefore this combination seems to be more appropriate in postmenopausal women with obesity and EAC. A clinical trial showed that long‐term metformin treatment can induce endometrial atrophy in 96% of women with endometrial hyperplasia. 110 The anticancer mechanism is mediated by inhibiting inflammatory signaling pathways, such as mammalian target of rapamycin (mTOR) and mitogen‐activated protein kinase (MAPK), which are involved in the pathogenesis of EAC. 106 A case–control study revealed that metformin inhibits the AKT/PI3K/mTOR signaling pathway in women with EAC compared to healthy controls. 107 These findings indicated that metformin through inhibition of furin, inflammatory signaling pathways, and growth factors may be effective in treating EAC. Statins are 3‐hydroxyl‐3‐methyl‐glutaryl coenzyme A (HMG‐CoA) reductase inhibit hepatic denovo cholesterol biosynthesis. 111 , 112 Statins are widely used in the management of hypercholesterolemia and dyslipidemia, therefore they are used in the prevention of primary and secondary cardiovascular complications. In addition, statins have anti‐inflammatory, antioxidant, anti‐thrombotic, and antiapoptotic effects. 113 Moreover, clinical studies established that statins have the ability to inhibit furin activity. 114 , 115 Furin plasma levels are increased in patients with acute cardiac events and following cardiac intervention in statins‐free patients but reduced in statins‐treated patients. 106 , 114 Higher plasma levels of furin and PCSK9 in patients with acute cardiac events are associated with resistance to statins therapy. 115 In addition, statins attenuate SARS‐CoV‐2 infection by inhibiting furin. 116 Interestingly, high cholesterol increases the activity of furin for priming and activation of SARS‐CoV‐2 spike protein to bind angiotensin‐converting enzyme 2 (ACE2). 117 Therefore, statins can directly inhibit furin or indirectly reduce furin activity by reducing cholesterol. On the other hand, statins can improve the survival of women patients with EAC by inhibiting endometrial cell proliferation and migration through modulation of the expression of furin. 118 , 119 However, long‐term use of statins led to borderline or ineffectiveness against the development and progression of EAC. 120 Statins have chemoprotective effects against EAC in high‐risk group women. 118 Findings from the Australian record linkage study demonstrated a potential benefit for statins use in women with EAC. 119 It has been reported women with EAC on statins therapy had a lower mortality rate compared to women not on statins therapy. 119 A retrospective study involved 985 women with EAC showed that statins improved survival and reduce complications. 121 In many epidemiological studies statins reduced EAC and ovarian risk, 122 however, statins were reported to be effective for ovarian but not for EAC. 123 However, a meta‐analysis and systematic review revealed that long‐term use of statins >5 years did not EAC risk. 124 These findings suggest that statins via inhibition of furin could be effective as adjuvant treatments in the management of EAC. Baicalein is a flavonoid isolated from Scutellaria lateriflora and Scutellaria balacalensis , has anti‐inflammatory, antioxidant, and anticancer effects. 125 Baicalein is regarded as an allosteric modulator of benzodiazepine receptors, and inhibits lipooxygenase. 126 It has been observed that baicalein has anticancer properties by numerous molecular mechanisms including inhibition of PI3K/AKT/mTOR, and MAPK. 127 Furthermore, baicalein inhibits adenosine diphosphate ribosylation factor 6, which promotes the proliferation and invasion of endometrial cancer cells. 128 Similarly, baicalein modulates the expression of progesterone receptors, which is intricate in the development of EAC. 129 Furthermore, baicalein attenuates the carcinogenesis of EAC by inhibiting the expression of inflammatory signaling pathways. 130 As baicalein is not clinically approved, therefore there are limitations regarding the clinical effects of baicalein in women with EAC. The underlying mechanism of baicalein in suppressing proliferation and invasion of EAC is not fully elucidated. However, inhibition of endometrial furin by baicalein could a possible mechanism. Preclinical studies illustrated that baicalein can inhibit endometrial proliferation and ectopic endometriosis by inducing apoptosis and expression of MMP and furin. 52 , 131 Therefore, furin inhibitor baicalein according to the preclinical findings seems to be effective against EAC. Taken together, furin inhibitors, such as metformin and statins could be a novel adjuvant therapeutic strategy in the management of EAC. The present review had several limitations including a paucity of clinical studies and the sequential level of furin in the different stages of EAC was not reviewed. However, this review highlighted the potential role of furin and associated inflammatory changes in the propagation of EAC. These findings indicated that furin inhibitors produce borderline effects in EAC. Therefore, this review exciting researchers in this field to perform future clinical trials, pilot, and prospective studies to confirm the exact role of furin in the pathogenesis of EAC regarding the efficacy and safety of furin inhibtors.

Hayder M. Al‐kuraishy, Thabat J. Al‐Maiahy, Ali I. Al‐Gareeb, Athanasios Alexiou : Conceptualization (lead); visualization; writing—original draft (lead). Marios Papadakis : writing—original draft (lead); funding acquisition (lead). Hebatallah M. Saad, Gaber El‐Saber Batiha : Conceptualization; supervision; resources (lead); writing—review and editing.

Not applicable.

Not applicable.

EAC is the most common malignant tumor of the female genital tract and is linked with menopause, obesity, and other cardiometabolic disorders. Furin is associated with the development and progression of EAC through induction of proliferation, invasion, and metastasis of malignant cells of EAC. Furin induces EAC through activation expression of ADAM17, pro‐renin receptor, CD109, and TGF‐β. As well, EAC‐mediated inflammation promotes expression of furin with further propagation of neoplastic growth and invasion. Taken together, furin has direct and indirect role in the advancement of EAC. Therefore, experimental and clinical studies are reasonable in this state to verify the potential role of furin in the development of EAC.

Endometrial adenocarcinoma (EAC) is a malignant tumor of the endometrium causing abnormal vaginal bleeding, dyspareunia, pelvic pain, and dysuria. 1 EAC is the most common female malignancy following the menopause period and presented with irregular vaginal bleeding and clear vaginal discharge. 1 About 40% of patients with EAC are linked with obesity. 1 , 2 As well, EAC is interrelated with hypertension, diabetes mellitus, and high circulating estrogen level. 3 EAC is the third greatest common cause of death in women following ovarian and cervical cancers. 1 , 3 EAC is the most common malignant tumor in developed countries and represents 80% of endometrial cancer. 4 Remarkably, the rate of EAC has been shown to increase between 1980 and 2020 due to the growing rate of obesity and the increasing rate of elderly women. 4 Regarding the molecular classification of EAC, recent studies illustrated four types including DNA polymerase epsilon (POLE) ‐mutated, copy number low, copy number high, and hypermutated type. 5 , 6 According to analogous classification system, five types are recorded including POLEmut, mismatch repair (MMR) deficient, p53 aberrant, and no specific molecular profile. 5 , 6 The National Comprehensive Cancer Network has integrated molecular analysis into its endometrial carcinoma algorithm as a result of the increasing amount of evidence that supports this classification system. 5 Diagnosis of EAC is done by endometrial biopsy. 4 Molecular biomarkers like DNA ploidy, hormone receptor, p53 level, stathmin, and level of adhesion molecules have been used in the diagnosis and prognosis of EAC. 4 Due to the heterogeneity of EAC, many molecular biomarkers might be not enough for a more accurate diagnosis of this type of malignancy. These methods are not “used” but they were “examined” as a screening serum marker. 7 Diagnosis should be confirmed by histopathologic examination of the endometrial biopsy, and it is the golden standard, and it can be applied as an office biopsy. Currently, there is no molecular diagnostic marker for any disease to replace histopathology. However many molecular markers are under examination for prognostic or therapeutic purposes mainly in EAC. This molecule may be high in endometrial cancer, however, to describe a diagnostic marker, and to report the presence or absence of a condition (here endometrial cancer) we need an accuracy test that describes the sensitivity, specificity, predictive values, and the likelihood ratios. 8 In order to render clinical judgments and direct the provision of patient treatment, healthcare professionals must possess a comprehensive grasp of the probability of a patient's affliction, achieved through the amalgamation of their understanding of pretest probability and diagnostic evaluations. Diagnostic instruments are regularly employed in healthcare environments for the purpose of ascertaining appropriate courses of action; nevertheless, numerous of these instruments are susceptible to fallacy. 8 The identification of EAC is conducted through the use of an endometrial biopsy. 4 Due to the heterogeneity of EAC, many molecular biomarkers might be not enough for a more accurate diagnosis of this type of malignancy. To promote the progress of clinical outcomes in women with EAC, numerous strategies are suggested to reach the primitive diagnosis of EAC particularly in the early stage. 9 Indeed, some biomarkers like micro‐RNA, miR223, miR222, and CA‐125 can accurately differentiate high and low‐risk women with EAC. 9 It has been shown that proprotein convertase (PC) furin was involved in different tumor progressions including EAC. 10 Different studies revealed that furin was the unique PC type linked with the development of EAC as confirmed by endometrial biopsies in postmenopausal women. 11 , 12 Thus, furin could be a noninvasive tool in the diagnosis of EAC. The rationale of the present study was regarded as due to the involvement of furin in various types of malignancies. 13 Therefore, furin could be a noninvasive tool in the diagnosis of EAC. Therefore, this review aimed to find the association between furin activity and EAC.

The authors have stated explicitly that there are no conflicts of interest in connection with this article.