Abstract
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 de-phosphorylation/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.
Highlights
Recent studies established the expression of functional membrane androgen receptors inducing rapid nongenomic androgen actions in tumors, including prostate [1,2], breast [3,4] and colon [5] as well as in other cell types such as macrophages and T cells [6,7], C6 [8] and vascular smooth muscle cells [9]
Additional control experiments performed by treatments either with testosterone not linked to human serum albumin (HSA) or HSA not linked to the androgen indicated clearly that long-term phosphorylated Akt (p-Akt) downregulation was not obvious when Caco2 cells were treated with testosterone (Supplemental Figure 1A)
This finding may seem contradictory to existing results with testosterone-HSA, it is consistent with a dual role of testosterone in simultaneous binding of membrane androgen receptors (mARs) and intracellular androgen receptors (iARs) within the same cell
Summary
Recent studies established the expression of functional membrane androgen receptors (mARs) inducing rapid nongenomic androgen actions in tumors, including prostate [1,2], breast [3,4] and colon [5] as well as in other cell types such as macrophages and T cells [6,7], C6 [8] and vascular smooth muscle cells [9]. The mAR-dependent nongenomic signaling was recently characterized in detail in prostate and breast cancer cells [15], and key prosurvival and proapoptotic gene products were identified that regulate the apoptotic response induced by mAR activation [16]. According to these reports it was postulated that mAR might be a significant novel target for cancer treatment. The proapoptotic responses were clearly dependent on mAR stimulation, downstream events regulating the expression and/or function of key prosurvival mediators in colon tumors remained undefined. The profound antitumorigenic mAR action has not been functionally correlated with changes in RESEARCH ARTICLE other key mechanisms such as cell motility and invasiveness
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