Membrane Androgen Receptor Down-Regulates c-Src-Activity and Beta-Catenin Transcription and Triggers GSK-3beta-Phosphorylation in Colon Tumor Cells

• Published in: Cellular physiology and biochemistry Vol. 34; no. 4; pp. 1402 - 1412
• Main Authors: Gu, Shuchen, Honisch, Sabina, Kounenidakis, Michalis, Alkahtani, Saad, Alarifi, Saud, Alevizopoulos, Konstantinos, Stournaras, Christos, Lang, Florian
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland Cell Physiol Biochem Press GmbH & Co KG 01-01-2014
• Subjects: Actin; Actin Cytoskeleton - genetics; Actin Cytoskeleton - metabolism; Albumins - genetics; Albumins - metabolism; Apoptosis - genetics; beta Catenin - genetics; beta Catenin - metabolism; Beta-catenin; c-Src; Caco-2 Cells; Cell Line, Tumor; Colon tumors; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Cyclin D1; Down-Regulation - genetics; Genes, src - genetics; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; GSK-3beta; Humans; mARs; Original Paper; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - genetics; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Signal Transduction - genetics; Testosterone - genetics; Testosterone - metabolism; Transcription, Genetic - genetics; c-Src; GSK-3beta; Beta-catenin; Actin; mARs; Colon tumors; Cyclin D1
• ISSN: 1015-8987; 1421-9778
• DOI: 10.1159/000366346

Background/Aims: Functional membrane androgen receptors (mARs) have recently been described in colon tumor cells and tissues. Their activation by specific testosterone albumin conjugates (TAC) down-regulates the PI-3K/Akt pro-survival signaling and triggers potent pro-apoptotic responses both, in vitro and in vivo. The present study explored the mAR-induced regulation of gene products implicated in the tumorigenic activity of Caco2 colon cancer cells. Methods: In Caco2 human colon cancer cells transcript levels were determined by RT-PCR, protein abundance and phosphorylation by Western blotting and confocal microscopy, as well as cytoskeletal architecture by confocal microscopy. Results: We report time dependent significant decrease in Tyr-416 phosphorylation of c-Src upon mAR activation. In line with the reported late down-regulation of the PI-3K/Akt pathway in testosterone-treated colon tumors, GSK-3beta was phosphorylated at Tyr-216 after long term stimulation of the cells with TAC, a finding supporting the role of this kinase to promote apoptosis. PCR analysis revealed significant decrease of beta-catenin and cyclin D1 transcript levels following TAC treatment. Moreover, confocal laser scanning microscopic analysis disclosed co-localization of beta-catenin with actin cytoskeleton. It is thus conceivable that beta-catenin may participate in the reported modulation of cytoskeletal dynamics in mAR stimulated Caco2 cells. Conclusions: Our results provide strong evidence that mAR activation regulates late expression and/or activity of the tumorigenic gene products c-Src, GSK-3beta, and beta-catenin thus facilitating the pro-apoptotic response in colon tumor cells.