IGF-IR Promotes Prostate Cancer Growth by Stabilizing α5β1 Integrin Protein Levels

Dynamic crosstalk between growth factor receptors, cell adhesion molecules and extracellular matrix is essential for cancer cell migration and invasion. Integrins are transmembrane receptors that bind extracellular matrix proteins and enable cell adhesion and cytoskeletal organization. They also mediate signal transduction to regulate cell proliferation and survival. The type 1 insulin-like growth factor receptor (IGF-IR) mediates tumor cell growth, adhesion and inhibition of apoptosis in several types of cancer. We have previously demonstrated that beta(1) integrins regulate anchorage-independent growth of prostate cancer (PrCa) cells by regulating IGF-IR expression and androgen receptor-mediated transcriptional functions. Furthermore, we have recently reported that IGF-IR regulates the expression of beta(1) integrins in PrCa cells. We have dissected the mechanism through which IGF-IR regulates beta(1) integrin expression in PrCa. Here we report that IGF-IR is crucial for PrCa cell growth and that beta(1) integrins contribute to the regulation of proliferation by IGF-IR. We demonstrate that beta(1) integrin regulation by IGF-IR does not occur at the mRNA level. Exogenous expression of a CD4 - beta(1) integrin cytoplasmic domain chimera does not interfere with such regulation and fails to stabilize beta(1) integrin expression in the absence of IGF-IR. This appears to be due to the lack of interaction between the beta(1) cytoplasmic domain and IGF-IR. We demonstrate that IGF-IR stabilizes the beta(1) subunit by protecting it from proteasomal degradation. The alpha(5) subunit, one of the binding partners of beta(1), is also downregulated along with beta(1) upon IGF-IR knockdown while no change is observed in the expression of the alpha(2), alpha(3), alpha(4), alpha(6) and alpha(7) subunits. Our results reveal a crucial mechanistic role for the alpha(5)beta(1) integrin, downstream of IGF-IR, in regulating cancer growth.