Insulin like growth factor 1 stimulation of androgen receptor activity requires b1A integrins
Despite the findings that b1 integrins play a vital role in the regulation of cell proliferation and survival, the mechanisms through which they operate and lead to cancer progression remain elusive. Previously, our laboratory has shown that b1A integrins support insulin like growth factor 1 (IGFI) mediated mitogenic and transforming activities. Here, we report that b1A integrins regulate basal levels of IGF IR, although they are not critical for maintaining cancer cell morphology. Upon transfection of b1A siRNA and consequent downregulation of IGF IR, we show inhibition of anchorage independent growth of prostate cancer cells, a function which is dependent on IGF IR expression. In addition, we demonstrate that IGFI mediated activation of androgen receptor (AR) known to occur in prostate cancer cells, requires expression of b1A integrins as evaluated by luciferase reporter assays and immunoblotting analysis. Since b1A integrin levels are increased by R1881 or dihydrotestosterone (DHT) our results imply that b1A integrins support an androgen enhanced feedback loop that regulates the expression of IGF IR. b1A integrins also regulate inducible levels of IGF IR in cells stimulated by androgen or by a combination of androgen and IGFI, as evaluated by flow cytometric analysis and immunoblotting. Furthermore, upon transfection of b1A siRNA and consequent downregulation of IGF IR, neither activation of AKT, an effector of IGF IR, nor AR levels are affected. We conclude that b1A integrin expression is critical for maintaining the regulatory crosstalk between IGF IR and AR. J. Cell. Physiol. 227: 751 758, 2012. (c) 2011 Wiley Periodicals, Inc.
Journal of cellular physiology