Thiazolidinediones inhibit insulin-like growth factor-i-induced activation of p70S6 kinase and suppress insulin-like growth factor-I tumor-promoting activity.
Thiazolidinediones are a novel class of antidiabetic drugs that improve insulin sensitivity in type 2 diabetic patients. Recently, these compounds have also been shown to suppress tumor development in several animal models. The molecular basis for their antitumor action, however, is largely unknown. We report here that oral administration of thiazolidinediones (rosiglitazone and troglitazone) remarkably inhibited insulin-like growth factor-I (IGF-I)-promoted skin tumor development by 73% in BK5.IGF-1 transgenic mice, although they were previously found to be ineffective in inhibiting UV- or chemically induced mouse skin tumorigenesis. The anti-IGF-I effect of troglitazone in mouse skin keratinocytes was due to, at least partially, inhibition of IGF-I-induced phosphorylation of p70S6 kinase (p70S6K) at Thr(389), a site specifically phosphorylated by mammalian target of rapamycin (mTOR). Troglitazone did not directly inhibit mTOR kinase activity as shown by mTOR in vitro kinase assay but rapidly activated AMP-activated protein kinase (AMPK) through a yet undefined peroxisome proliferator-activated receptor gamma-independent mechanism. Expression of a dominant-negative AMPK reversed the inhibitory effect of troglitazone on IGF-I-induced phosphorylation of p70S6K, suggesting that troglitazone inhibited IGF-I and p70S6K signaling through activation of AMPK. Collectively, these data suggest that thiazolidinediones specifically inhibit IGF-I tumor-promoting activity in mouse skin through activation of AMPK and subsequent inhibition of p70S6K.
He
Guobin
G
Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, 1808 Park Road 1C, Smithville, TX 78957, USA.
Sung
You Me
YM
Digiovanni
John
J
Fischer
Susan M
SM
D055372:AMP-Activated Protein Kinases; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D058570:TOR Serine-Threonine Kinases; D045162:Thiazolidinediones / Q000494:pharmacology*; D014162:Transfection; D000077288:Troglitazone
D000970:Antineoplastic Agents; D002839:Chromans; D009097:Multienzyme Complexes; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D007334:Insulin-Like Growth Factor I; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000077288:Troglitazone