BackgroundMembrane androgen receptors (mAR) have been implicated in the regulation of cell growth, motility and apoptosis in prostate and breast cancer. Here we analyzed mAR expression and function in colon cancer.ResultsUsing fluorescent mAR ligands we showed specific membrane staining in colon cell lines and mouse xenograft tumor tissues, while membrane staining was undetectable in healthy mouse colon tissues and non-transformed intestinal cells. Saturation/displacement assays revealed time- and concentration-dependent specific binding for testosterone with a KD of 2.9 nM. Stimulation of colon mAR by testosterone albumin conjugates induced rapid cytoskeleton reorganization and apoptotic responses, even in the presence of anti-androgens. The actin cytoskeleton drug cytochalasin B effectively inhibited the pro-apoptotic responses and caspase-3 activation. Interestingly, in vivo studies revealed that mAR activation resulted in a 65% reduction of tumor incidence in chemically induced Balb/c mice colon tumors.ConclusionOur results demonstrate for the first time that functional mARs are predominantly expressed in colon tumors and that their activation results in induction of anti-tumor responses in vitro and extensive reduction of tumor incidence in vivo.
Recently, we reported that membrane androgen receptors (mARs) are expressed in colon tumors triggering strong apoptotic responses. In the present study, we analyzed mAR-induced downstream effectors controlling cell survival and migration of Caco2 colon cancer cells. We show that long-term activation of mAR downregulated the activity of PI-3K and Akt and induced dephosphorylation/activation of the proapoptotic Bad (p-Bad). Moreover, treatment of APC Min/+ mice, which spontaneously develop intestinal tumors, with mAR-activating testosterone conjugates reduced the tumor incidence by 80% and significantly decreased the expression of p-Akt and p-Bad levels in tumor tissue. Furthermore, mAR activation strongly inhibited Caco2 cell migration. In accordance with these findings, vinculin, a protein controlling cell adhesion and actin reorganization, was effectively phosphorylated upon mAR activation. Phosphorylation inhibitors genistein and PP2 inhibited actin reorganization and restored motility. Moreover, silencing vinculin by appropriate siRNA's, or blocking actin reorganization by cytochalasin B, restored the migration potential. From these results we conclude that mAR activation inhibits the prosurvival signals Akt/Bad in vitro and in vivo and blocks migration of colon cancer cells via regulation of vinculin signaling and actin reorganization, supporting the powerful tumoristatic effect of those receptors.
Background: Recently we have reported membrane androgen receptors-induced apoptotic regression of prostate cancer cells regulated by Rho/ROCK/actin signaling. In the present study we explored the specificity of these receptors and we analyzed downstream effectors controlling survival and apoptosis in hormone refractory DU145-prostate cancer cells stimulated with membrane androgen receptor-selective agonists.
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