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Molecular Medicine

, Volume 17, Issue 1–2, pp 48–58 | Cite as

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

  • Shuchen Gu
  • Natalia Papadopoulou
  • Omaima Nasir
  • Michael Föller
  • Konstantinos Alevizopoulos
  • Florian Lang
  • Christos Stournaras
Research Article

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 dephosphorylation/activation of the proapoptotic Bad (p-Bad). Moreover, treatment of APCMin/+ 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.

Notes

Acknowledgements

This work was supported by grants from Deutsche Forschungsgemeinschaft (GRK 1302; SFB773; Mercator program) and the Greek Ministry of Health (KESY program).

Supplementary material

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Supplementary material, approximately 116 KB.

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Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Shuchen Gu
    • 1
  • Natalia Papadopoulou
    • 2
  • Omaima Nasir
    • 1
  • Michael Föller
    • 1
  • Konstantinos Alevizopoulos
    • 3
  • Florian Lang
    • 1
  • Christos Stournaras
    • 1
    • 2
  1. 1.Department of PhysiologyUniversity of TubingenTubingenGermany
  2. 2.Department of BiochemistryUniversity of Crete Medical SchoolHeraklionGreece
  3. 3.Medexis-Biotech SAKryoneri AthensGreece

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