β1A integrin expression is required for type 1 insulin-like growth factor receptor mitogenic and transforming activities and localization to focal contacts

Academic Article

Abstract

  • The cells' ability to proliferate in response to growth factor stimulation is significantly altered during cancer progression. To investigate the mechanisms underlying these alterations in prostate cancer, the role and expression of β integrin and type 1 insulin-like growth factor receptor (IGF-IR), known to contribute to cell proliferation and transformation, were analyzed. Using small interfering RNA oligonucleotides to down-regulate β , we show that β expression is required for IGF-IR-mediated prostate cancer cell proliferation and anchorage-independent growth. In vivo, using age-matched transgenic adenocarcinoma of mouse prostate (TRAMP) mice at different stages of prostate cancer [prostatic intraepithelial neoplasia, PIN; well-differentiated adenocarcinoma, WD; and poorly differentiated adenocarcinoma, PD], the expression of β and of IGF-IR was studied. β and IGF-IR expression levels were concurrently up-regulated in high PIN and WD, whereas their expression did not correlate in late-stage PD. In contrast to the up-regulated expression of β , the levels of β , a β cytoplasmic variant that inhibits cell proliferation, were down-regulated in all stages of prostate cancer. A similar expression pattern was observed for a β downstream effector, Grb2-associated binder-1 (Gab1) which is known to inhibit IGF-IR phosphorylation. To analyze in vitro the mechanistic implications of β , β , and Gab1 deregulation in prostate cancer, we investigated whether expression of either β variant in β -null cells affected IGF-IR localization. We found that IGF-IR and β were colocalized in highly specialized integrin signaling compartments, designated focal contacts. However, in the presence of β , IGF-IR remained diffuse on the cell surface and did not localize to focal contacts. The findings that β integrins and IGF-IR are concurrently deregulated and that expression of β integrins is necessary to achieve appropriate IGF-IR intracellular distribution point to the important role that the cross-talk between these receptors may have during prostate cancer progression and will be helpful in formulating new therapeutic strategies. ©2005 American Association for Cancer Research. 1A 1A 1A 1A 1A 1A 1C 1 1C 1A 1C 1 1 1A 1C 1 1
  • Authors

    Published In

  • Cancer Research  Journal
  • Digital Object Identifier (doi)

    Author List

  • Goel HL; Breen M; Zhang J; Das I; Aznavoorian-Cheshire S; Greenberg NM; Elgavish A; Languino LR
  • Start Page

  • 6692
  • End Page

  • 6700
  • Volume

  • 65
  • Issue

  • 15