α3β1 Integrin Suppresses Prostate Cancer Metastasis via Regulation of the Hippo Pathway

Cancer Res. 2016 Nov 15;76(22):6577-6587. doi: 10.1158/0008-5472.CAN-16-1483. Epub 2016 Sep 28.

Abstract

Existing anticancer strategies focused on disrupting integrin functions in tumor cells or tumor-involved endothelial cells have met limited success. An alternative strategy is to augment integrin-mediated pathways that suppress tumor progression, but how integrins can signal to restrain malignant behavior remains unclear. To address this issue, we generated an in vivo model of prostate cancer metastasis via depletion of α3β1 integrin, a correlation observed in a significant proportion of prostate cancers. Our data describe a mechanism whereby α3β1 signals through Abl family kinases to restrain Rho GTPase activity, support Hippo pathway suppressor functions, and restrain prostate cancer migration, invasion, and anchorage-independent growth. This α3β1-Abl kinase-Hippo suppressor pathway identified α3 integrin-deficient prostate cancers as potential candidates for Hippo-targeted therapies currently under development, suggesting new strategies for targeting metastatic prostate cancer based on integrin expression. Our data also revealed paradoxical tumor suppressor functions for Abl kinases in prostate cancer that may help to explain the failure of Abl kinase inhibitor imatinib in prostate cancer clinical trials. Cancer Res; 76(22); 6577-87. ©2016 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Humans
  • Integrin alpha3beta1 / genetics*
  • Male
  • Mice
  • Neoplasm Metastasis
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction

Substances

  • Integrin alpha3beta1
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases