Thiazolidinediones inhibit insulin-like growth factor-I-induced activation of p70S6 kinase and suppress insulin-like growth factor-I tumor-promoting activity
Thiazolidinediones inhibit insulin-like growth factor-I-induced activation of p70S6 kinase and suppress insulin-like growth factor-I tumor-promoting activity
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DOI：
10.1158/0008-5472.can-05-3111
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发表时间：
2006-02-01
期刊：
影响因子：
11.2
通讯作者：
Fischer, SM
中科院分区：
文献类型：
--
作者：
He, GB;Sung, YM;Fischer, SM
噻唑烷二酮类药物是一类新型抗糖尿病药物，可改善2型糖尿病患者的胰岛素敏感性。最近，这些化合物也被证明可以在几种动物模型中抑制肿瘤的发展。然而，其抗肿瘤作用的分子基础在很大程度上是未知的。我们在这里报告，口服噻唑烷二酮类药物（罗格列酮和曲格列酮）显着抑制胰岛素样生长因子-I（IGF-I）促进皮肤肿瘤的发展73%的BK 5。IGF-I转基因小鼠，虽然他们以前被发现是无效的抑制紫外线或化学诱导的小鼠皮肤肿瘤发生。曲格列酮在小鼠皮肤角质形成细胞中的抗IGF-I作用至少部分是由于抑制IGF-I诱导的Thr（389）处p70 S6激酶（p70 S6 K）的磷酸化，Thr（389）是一个被哺乳动物雷帕霉素靶蛋白（mTOR）特异性磷酸化的位点。如mTOR体外激酶试验所示，曲格列酮不直接抑制mTOR激酶活性，但通过尚未确定的过氧化物酶体增殖物激活受体γ-非依赖性机制快速激活AMP激活蛋白激酶（AMPK）。显性负性AMPK的表达逆转了曲格列酮对IGF-I诱导的p70 S6 K磷酸化的抑制作用，表明曲格列酮通过激活AMPK抑制IGF-I和p70 S6 K信号传导。总的来说，这些数据表明噻唑烷二酮类通过激活AMPK和随后抑制p70 S6 K特异性抑制小鼠皮肤中的IGF-I肿瘤促进活性。
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-I 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 y-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.