The Effects of Adiponectin and Metformin on Prostate and Colon Neoplasia Involve Activation of AMP-Activated Protein Kinase
The Effects of Adiponectin and Metformin on Prostate and Colon Neoplasia Involve Activation of AMP-Activated Protein Kinase
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DOI：
10.1158/1940-6207.capr-08-0081
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发表时间：
2008-10-01
影响因子：
3.3
通讯作者：
Pollak, Michael N.
中科院分区：
文献类型：
--
作者：
Zakikhani, Mahvash;Dowling, Ryan J. O.;Pollak, Michael N.
人群研究提供的证据表明，肥胖和胰岛素抵抗不仅与血清胰岛素水平升高和血清脂联素水平降低有关，而且与侵袭性前列腺癌和结肠癌的风险增加有关。我们在这里显示，脂联素激活AMP激活蛋白激酶（AMPK）在结肠癌（HT-29）和前列腺癌（PC-3）细胞。这些结果与先前在肌细胞中的观察结果一致，但我们表明，在上皮癌细胞中，AMPK活化与雷帕霉素活化的哺乳动物靶标的减少相关，如通过Ser（2448）磷酸化估计的，与p70 S6激酶活化的减少相关，如通过Thr（389）磷酸化估计的，与核糖体蛋白S6活化相关，如通过Ser（235/236）磷酸化估计的，通过[S-35]甲硫氨酸掺入估计蛋白质翻译减少，并具有生长抑制。当使用小干扰RNA降低AMPK水平时，脂联素诱导的生长抑制显著减弱，表明AMPK参与介导这种脂肪因子的抗增殖作用。因此，脂联素具有AMPK依赖性生长抑制剂的特征，在肥胖症中缺乏，这可能有助于肥胖症对肿瘤疾病的不利影响。此外，二甲双胍被观察到激活AMPK并对前列腺癌和结肠癌细胞具有生长抑制作用，这表明该化合物可能在减轻肥胖对肿瘤形成的不利影响方面具有特别的价值。
Population studies provide evidence that obesity and insulin resistance are associated not only with elevated serum insulin levels and reduced serum adiponectin levels but also with increased risk of aggressive prostate and colon cancer. We show here that adiponectin activates AMP-activated protein kinase (AMPK) in colon (HT-29) and prostate (PC-3) cancer cells. These results are consistent with prior observations in myocytes, but we show that in epithelial cancer cells AMPK activation is associated with reduction in mammalian target of rapamycin activation as estimated by Ser(2448) phosphorylation, with reduction in p70S6 kinase activation as estimated by Thr(389) phosphorylation, with ribosomal protein S6 activation as estimated by Ser(235/236) phosphorylation, with reduction in protein translation as estimated by [S-35] methionine incorporation, and with growth inhibition. Adiponectin-induced growth inhibition is significantly attenuated when AMPK level is reduced using small interfering RNA, indicating that AMPK is involved in mediating the antiproliferative action of this adipokine. Thus, adiponectin has the characteristics of a AMPK-dependent growth inhibitor that is deficient in obesity, and this may contribute to the adverse effects of obesity on neoplastic disease. Furthermore, metformin was observed to activate AMPK and to have growth inhibitory actions on prostate andcolon cancer cells, suggesting that this compound may be of particular value in attenuating the adverse effects of obesity on neoplasia.