Adiponectin signals in prostate cancer cells through Akt to activate the mammalian target of rapamycin pathway
Adiponectin signals in prostate cancer cells through Akt to activate the mammalian target of rapamycin pathway
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DOI：
10.1677/erc-06-0091
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发表时间：
2007-12-01
影响因子：
3.9
通讯作者：
Balk, S. P.
中科院分区：
文献类型：
--
作者：
Barb, D.;Neuwirth, A.;Balk, S. P.
脂联素因其对胰岛素敏感性的有益作用而备受关注，流行病学研究进一步表明，脂联素水平与多发性肿瘤的风险呈负相关，这种相关性独立于IGF系统或其他危险因素。先前的研究表明，脂联素可以激活心肌细胞、肝细胞和脂肪细胞中的AMP激活的蛋白激酶(AMPK)，提示脂联素可能通过激活AMPK进而抑制哺乳动物雷帕霉素靶点(MTOR)来抑制肿瘤的发展。然而，脂联素影响癌细胞的机制尚不清楚，而且在所有类型的细胞中，尤其是在癌细胞中，脂联素是否与相同的下游靶点相关联仍有待确定。在目前的研究中，我们证明了脂联素在刺激磷酸酶和张力蛋白同源缺失的十号染色体(PTEN)缺失的LNCaP前列腺癌细胞中AMPK的同时，它也增加了mTOR活性，这是通过两个下游靶标p70 S6激酶和核糖体蛋白S6的磷酸化来评估的。这种脂联素对mTOR的刺激是通过磷脂酰肌醇3-激酶(PI3激酶)和Akt激活来实现的。这些结果表明，脂联素可以激活AMPK和PI3激酶/Akt通路，细胞类型的特定因素，如PTEN状态，可能决定这些通路中的哪一条将对mTOR起主导作用。因此，虽然高水平的内源性脂联素可能通过直接机制或间接全身机制来预防癌症，但我们的结果表明，脂联素也可能直接刺激信号通路，促进某些肿瘤的生长。
Adiponectin has received much attention due to its beneficial effects on insulin sensitivity, and epidemiologic studies have further shown an inverse association between adiponectin levels and risk for multiple tumors, which is independent of the IGF system or other risk factors. Previous studies have shown that adiponectin can activate AMP-activated protein kinase (AMPK) in myocytes, hepatocytes, and adipocytes, suggesting that adiponectin may suppress tumor development through AMPK activation and subsequent inhibition of mammalian target of rapamycin (mTOR). However, the mechanisms through which adiponectin affects cancer cells are not understood, and it remains to be determined whether adiponectin is linked to the same downstream targets in all cells types, and in particular in cancer cells. In the present study, we demonstrate that while adiponectin stimulates AMPK in phosphatase and tensin homolog deleted on chromosome ten (PTEN) deficient LNCaP prostate cancer cells, it also increases mTOR activity as assessed by phosphorylation of two downstream targets, p70 S6 kinase and ribosomal protein S6. This adiponectin stimulation of mTOR was mediated through phosphatidylinositol 3-kinase (PI3 kinase) and Akt activation. These results show that adiponectin can activate both AMPK and PI3 kinase/Akt pathways, and that cell type-specific factors such as PTEN status may determine which of these pathways will have the dominant effect on mTOR. Therefore, while it is possible that high endogenous adiponectin levels could be protective against cancer by direct mechanisms or indirect systemic mechanisms, our results indicate that adiponectin may also directly stimulate signaling pathways that enhance the growth of some tumors.