Beta1 integrins mediate cell proliferation in three-dimensional cultures by regulating expression of the sonic hedgehog effector protein, GLI1

Abstract

The beta1 integrins play an important role in the modulation of cancer cell proliferation and tumor growth. We have previously shown that beta1 integrins associate with insulin-like growth factor type 1 receptor (IGF-IR) and regulate IGF-stimulated prostate cancer cell proliferation. In the present study, we find that downregulation of beta1 in prostate cancer cells inhibits IGF-IR and AKT activation. We also show that beta1 downregulation in two- and three-dimensional (3D) prostate cancer cell cultures significantly reduces expression of GLI1, a transcription factor known to be regulated by the IGF/AKT signaling pathway and to be a downstream effector of sonic hedgehog. Re-expression of GLI1 rescues the inhibitory effect of beta1 downregulation on prostate cancer cell proliferation in 3D cultures. We find that downregulation of beta1 significantly reduces surface expression of the associated alpha 5 integrin subunit. Our results indicate that the beta1/IGF-IR complex regulates expression of GLI1, which in turn promotes cancer cell proliferation in 3D cultures.