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

Abstract

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 β1 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 β1 integrins in PrCa cells. We have dissected the mechanism through which IGF-IR regulates β1 integrin expression in PrCa. Here we report that IGF-IR is crucial for PrCa cell growth and that β1 integrins contribute to the regulation of proliferation by IGF-IR. We demonstrate that β1 integrin regulation by IGF-IR does not occur at the mRNA level. Exogenous expression of a CD4 - β1 integrin cytoplasmic domain chimera does not interfere with such regulation and fails to stabilize β1 integrin expression in the absence of IGF-IR. This appears to be due to the lack of interaction between the β1 cytoplasmic domain and IGF-IR. We demonstrate that IGF-IR stabilizes the β1 subunit by protecting it from proteasomal degradation. The α5 subunit, one of the binding partners of β1, is also downregulated along with β1 upon IGF-IR knockdown while no change is observed in the expression of the α2, α3, α4, α6 and α7 subunits. Our results reveal a crucial mechanistic role for the α5β1 integrin, downstream of IGF-IR, in regulating cancer growth.

The αvβ6 Integrin Is Transferred Intercellularly via Exosomes

“…Quantitative Real Time PCR-Quantitative real time (qRT) PCR analysis was performed as described earlier (37). Each reaction was carried out, at least in triplicate; standard deviations were calculated using Excel (Microsoft) software.…”

Function of insulin‑like growth factor 1 receptor in cancer resistance to chemotherapy (Review)

“…Previous studies have indicated that IGF1R stabilizes the molecular structure of β1 integrin by protecting it from proteasomal degradation and promoting tumor cells to grow and proliferate (93). FAK, a substrate protein of IGF1R, is activated by integrin, affecting epithelial transformation, invasion and metastasis of tumor cells IGF1R-independently (38).…”

Role of CD154 in cancer pathogenesis and immunotherapy

“…It is worth noting at this point that the newly identified receptors of CD154 alone or in combination with CD40 could be at play in the CD154-mediated tumorigenic activity. Indeed, the a5b1 and the aMb2 integrins have been described as contributors to the pathogenesis of several types of cancers by interacting with their classical ligands, namely the fibronectin and intercellular adhesion molecule-1 (ICAM-1), respectively [30][31][32][33][34][35][36].…”