Effect of insulin-like growth factor II on protecting myoblast cells against cisplatin-induced apoptosis through p70 S6 kinase pathway.
Insulin-like growth factor (IGF-II) is overexpressed in a variety of human tumors and has both mitogenic and antiapoptotic activity. Although the mechanisms of IGF-II-induced proliferation have been well studied, the mechanisms underlying its survival signaling have been less well characterized. In this report, we investigated the role of IGF-II on cisplatin-induced apoptosis. We found that IGF-II overexpression was associated with an increase in p70 ribosomal protein S6 kinase (p70 S6K). Cisplatin treatment of C2C12 mouse myoblasts led to cell death associated with an inhibition of p70 S6K activity. Endogenous or exogenous IGF-II addition to C2C12 cells caused protection to cisplatin-induced apoptosis. This protection was associated in both cases with an increase in p70 S6K basal activity as well as resistance to cisplatin-induced decreased activity. Blockade of p70 S6K activation by rapamycin abrogated the IGF-II-mediated protection of cells to cisplatin-induced apoptosis. Furthermore, treatment of IGF-II-overexpressing Rh30 and CTR rhabdomyosarcoma cells with rapamycin restored sensitivity to cisplatin-induced apoptosis. These data together suggest that IGF-II-associated protection to cisplatin-induced apoptosis is mediated through an activation of the p70 S6K pathway. Thus, inhibition of the p70 S6 pathway may enhance chemotherapy-induced apoptosis in the treatment of IGF-II-overexpressing tumors.
Molecular Oncology Section, Pediatric Oncology Branch, NCI, National Institutes of Health, Bethesda, MD 20892-1928, USA.
Xiaolin
X
Wan
Lee J
LJ
Helman
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D018797:Cell Cycle Proteins; D002455:Cell Division; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D019610:Cytoprotection; D019008:Drug Resistance, Neoplasm; D039642:Eukaryotic Initiation Factors; D005434:Flow Cytometry; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D051379:Mice; D032446:Myoblasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D012208:Rhabdomyosarcoma / Q000188:drug therapy; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; D007335:Insulin-Like Growth Factor II; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D002945:Cisplatin; D020123:Sirolimus