Androgen Plays a Carcinogenic Role in EOC via the PI3K/AKT Signaling Pathway in an AR-Dependent Manner

Abstract

Background: Epithelial ovarian cancer (EOC) is one of the most common gynecological cancers with the highest mortality rate. Studies indicate that androgens contribute to initiation or progression of EOC through poorly understood mechanisms, however, in the phase II clinical studies of antiandrogen therapy for EOC, neither flutamide nor bicalutamide showed good antitumor effects. Based on the contradictions, the purpose of this study was to explore the role of androgen receptor (AR) in the androgen pathogenesis of EOC and the possible mechanism, and further to find an indicator to screen the anti-androgen therapy sensitive cases. Methods: In this study, 70 EOC biopsies and 17 para-cancerous tissues with complete medical information were collected and analyzed. The expression of the androgen receptor (AR) was detected by immunohistochemistry. In addition, ovarian cancer cell lines were used for in vitro studies to further explore the role of androgen in cell proliferation and the possible mechanisms. Results: The results showed that the expression of AR in ovarian cancer tissues was significantly elevated compared to the para-cancerous tissues, particularly in low-grade EOC, and the presence of high AR expression often suggested a worse prognosis. The in vitro study indicated that testosterone promoted the proliferation of the AR-positive SKOV3 cell line, which could be blocked by flutamide, but not in the AR-negative A2780 cell line. Next, we showed that testosterone-promoted proliferation in SKOV3 cells was abolished after we knocked out the AR. The mechanism studies revealed that the p-AKT expression in the ovarian cancer tissue was increased compared to the para-cancerous tissues, following a pattern similar to the increase of AR expression. Furthermore, the deletion and overexpression of SKOV3 cells' ARs lead to corresponding changes in the p-AKT levels. In addition, the BEZ235, an inhibitor of the PI3K/AKT signaling pathway blocked the proliferative effect of testosterone in SKOV3 cells. Conclusion: We showed that testosterone was able to promote the proliferation of ovarian cancer cells through activating the PI3K/AKT signaling pathway in an AR dependent manner and AR may be a screening indicator for anti-androgen therapy sensitive cases of EOC.

Diane-35 and metformin therapy in rats with endometrial lesions induced by dihydrotestosterone exposure

“…AR plays an important role in the occurrence and development of sex hormone-dependent tumors. Some studies have indicated that androgen can mediate the overactivation of the phosphatidylinositol-4,5-bisphosphate3-kinase-protein kinase B (PI3K/Akt) signaling pathway and thus promote the proliferation of ovarian cancer cells in an AR-dependent manner ( 44 ). In addition, AR is highly expressed in breast cancer and has carcinogenic potential in ERα-negative breast cancer.…”

Screening and Identification of a Prognostic Model of Ovarian Cancer by Combination of Transcriptomic and Proteomic Data

“…We also found that AR could bind directly to the IL12A promoter region to repress transcription, thereby suppressing the cytotoxicity of IL-12-activated NK cells in HCC [ 45 ]. As has been highlighted by scholars, ovarian cancer cell proliferation can also be mediated by the androgen/AR-independent activation of PI3K/AKT [ 46 ].…”