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Activation of membrane androgen receptors in colon cancer inhibits the prosurvival signals Akt/bad in vitro and in vivo and blocks migration via vinculin/actin signaling.

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.

SUBMITTER: Gu S

PROVIDER: S-EPMC3022983 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe cytoskeletal adaptor protein vinculin plays a fundamental role in cell contact regulation and affects central aspects of cell motility, which are essential to both embryonal development and tissue homeostasis. Functional regulation of this evolutionarily conserved and ubiquitously expressed protein is dominated by a high-affinity, autoinhibitory head-to-tail interaction that spatially restricts ligand interactions to cell adhesion sites and, furthermore, limits the residency time of vinculin at these sites. To date, no mutants of the vinculin protein have been characterized in animal models.Methodology/principal findingsHere, we investigate vinculin-DeltaEx20, a splice variant of the protein lacking the 68 amino acids encoded by exon 20 of the vinculin gene VCL. Vinculin-DeltaEx20 was found to be expressed alongside with wild type protein in a knock-in mouse model with a deletion of introns 20 and 21 (VCL-DeltaIn20/21 allele) and shows defective head-to-tail interaction. Homozygous VCL-DeltaIn20/21 embryos die around embryonal day E12.5 showing cranial neural tube defects and exencephaly. In mouse embryonic fibroblasts and upon ectopic expression, vinculin-DeltaEx20 reveals characteristics of constitutive head binding activity. Interestingly, the impact of vinculin-DeltaEx20 on cell contact induction and stabilization, a hallmark of the vinculin head domain, is only moderate, thus allowing invasion and motility of cells in three-dimensional collagen matrices. Lacking both F-actin interaction sites of the tail, the vinculin-DeltaEx20 variant unveils vinculin's dynamic binding to cell adhesions independent of a cytoskeletal association, and thus differs from head-to-tail binding deficient mutants such as vinculin-T12, in which activated F-actin binding locks the protein variant to cell contact sites.Conclusions/significanceVinculin-DeltaEx20 is an active variant supporting adhesion site stabilization without an enhanced mechanical coupling. Its presence in a transgenic animal reveals the potential of splice variants in the vinculin gene to alter vinculin function in vivo. Correct control of vinculin is necessary for embryonic development.

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Activation of membrane androgen receptors in colon cancer inhibits the prosurvival signals Akt/bad in vitro and in vivo and blocks migration via vinculin/actin signaling.

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