IGF-IR Promotes Prostate Cancer Growth by Stabilizing α(5)β(1) 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 β(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 β(1) integrins in PrCa cells. We have dissected the mechanism through which IGF-IR regulates β(1) integrin expression in PrCa. Here we report that IGF-IR is crucial for PrCa cell growth and that β(1) integrins contribute to the regulation of proliferation by IGF-IR. We demonstrate that β(1) integrin regulation by IGF-IR does not occur at the mRNA level. Exogenous expression of a CD4 - β(1) integrin cytoplasmic domain chimera does not interfere with such regulation and fails to stabilize β(1) integrin expression in the absence of IGF-IR. This appears to be due to the lack of interaction between the β(1) cytoplasmic domain and IGF-IR. We demonstrate that IGF-IR stabilizes the β(1) subunit by protecting it from proteasomal degradation. The α(5) subunit, one of the binding partners of β(1), is also downregulated along with β(1) upon IGF-IR knockdown while no change is observed in the expression of the α(2,) α(3,) α(4,) α(6) and α(7) subunits. Our results reveal a crucial mechanistic role for the α(5)β(1) integrin, downstream of IGF-IR, in regulating cancer growth.