Testosterone induced apoptosis in colon cancer cells is regulated by PI3K/Rac1 signaling

Abstract

Recently, it has been reported that testosterone membrane signaling regulates actin reorganization and induces pro-apoptotic responses in colon tumor cells. In the present study the membrane androgen receptors (mARs)-induced activation of Rac1 GTPase and the involvement of PI3K/Rac1 signaling in controlling the apoptotic responses in testosterone treated Caco2 colon cancer cells has been analyzed. In line with previous findings, activation of mAR by testosterone conjugates triggered early and transient actin reorganization as indicated by the significant decrease of the G/Total actin ratio after 15-and 30-min treatment of the cells. Interestingly, stimulation of mAR rapidly activated the Rac1 GTPase. This effect was evident after 15 min and persisted for at least 24 h. Testosterone induced Rac1 activation was fully blocked in Caco2 cells pre-treated with the PI3K inhibitor wortmannin, indicating that Rac1 signaling is acting downstream of the PI3K pathway. Remarkably, when cells were pre-treated with wortmannin that blocks the PI3K/Rac1 signaling, apoptotic response was almost fully inhibited. These finding suggest that Rac1 activation, triggering actin redistribution, is involved in testosterone induced pro-apoptotic responses governed by mAR activation and emphasize the regulatory role of PI3K/Rac1 signaling in colon tumors.

The actin cytoskeleton in rapid steroid hormone actions

“…In line with the reports in prostate cancer cells, in the breast cancer cell lines T47D and MDA-MB-231 the testosterone-induced apoptosis was also shown to be mediated by Rho/actin signaling [Pelekanou et al, 2010]. Finally, androgen stimulated actin cytoskeleton reorganization in Caco2 and HCT116 colon tumor cells, controlled by FAK/PI3K/mTOR/PAK1 [Gu et al, 2013] or PI3K/ Rac1 [Alkahtani, 2013] signaling, was also involved in the apoptotic responses [Gu et al, 2009;Alkahtani, 2013], since the drug cytochalasin B or the PI3K inhibitor wortmannin effectively inhibited pro-apoptotic signaling.…”

“…As discussed above, recent observations showed that actin reorganization initiated by steroids hormones, including glucocorticoids and androgens is controlling various cellular functions such as secretion, apoptotic responses and migratory potential in membrane hormone receptor‐stimulated human cancer cells [Charalampopoulos et al, ; Fu and Simoncini, ; Mayanagi et al, ; Papadopoulou et al, ; Gu et al, ; Fu et al, ; Pelekanou et al, ; Alkahtani, ]. These studies clearly establish a pivotal role of actin signaling linking membrane‐initiated, steroid hormone actions and regulation of cellular response mechanisms in different cancer cell types.…”

The Regulation of Steroid Action by Sulfation and Desulfation

“…However, the effect of androgens in CRC is unclear. In vitro T induced apoptosis in CRC cell lines ( 315 , 368 ), whereas DHEA enhances survival ( 315 ). In contrast, Tutton and Barkla ( 369 ) found that in vivo administration of T accelerated cell proliferation in the small intestine and induced colon cancer in rats, with CRC growth reduced after castration.…”

Sexual dimorphism of colorectal cancer in humans and colorectal tumors in a murine model

“…The concentration of sex steroids is one of the most important intrinsic factors that differ between both sexes 3 ; these molecules have important roles in the gut: Estrogens influence epithelial membrane permeability, serotonin production, expression of tight junctions, inflammation, and microbiome composition 4 ; Androgens are poorly understood; however, in a mouse model alters the proliferation of enterocytes and increases the size of crypts 5 . Further in vitro studies with colon cancer cell lines such as DLD-1, HCT-116, SW480, and CaCO2 have shown that estradiol reduces the viability of these cells, and testosterone (T4) and dihydrotestosterone (DHT) increase the apoptosis in CaCO2 and HCT116 [6][7][8][9][10][11][12][13][14][15] .…”