The phosphatidylinositol-3 kinase pathway is not essential for insulin-like growth factor I receptor-mediated clonogenic radioresistance.
The insulin-like growth factor I receptor (IGF-IR) is known to induce clonogenic radioresistance in cells following ionizing irradiation. To explore the downstream signaling pathways, we focused on the phosphatidylinositol-3 kinase (PI3-K) pathway, which is thought to be the primary cell survival signal originating from the receptor. For this purpose, R- cells deficient in the endogenous IGF-IR were used as a recipient of the human IGF-IR with or without mutations at potential PI3-K activation sites: NPXY950 and Y1316XXM. Mutants with double mutation at Y950/Y1316 exhibited not abrogated, but reduced activation of IRS-1, PI3-K, and Akt upon IGF-I stimulation. However, the mutants had the same clonogenic radioresistance as cells with wild type (WT) receptors. Neither wortmannin nor LY294002, specific inhibitors of PI3-K, affected the radioresistance of cells with WT receptors at concentrations specific for PI3-K. Collectively, these results indicate that the PI3-K pathway is not essential for IGF-IR-mediated clonogenic radioresistance.
Dong
Yu
Y
Molecular Diagnosis and Therapeutics, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku,Tokyo 113-5803, Japan.
Watanabe
Hiroshi
H
Shibuya
Hitoshi
H
Miura
Masahiko
M
D000818:Animals; D002460:Cell Line; D002999:Clone Cells / Q000528:radiation effects; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011836:Radiation Tolerance / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000502:physiology*
D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1