Phosphatidic acid signaling to mTOR: signals for the survival of human cancer cells.
Phosphatidic acid signaling to mTOR: signals for the survival of human cancer cells.
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DOI：
10.1016/j.bbalip.2009.02.009
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发表时间：
2009-09
期刊：
影响因子：
--
通讯作者：
Foster DA
中科院分区：
文献类型：
--
作者：
Foster DA
在过去十年中，几乎所有检查过的癌症中都报道了磷脂酶 D (PLD) 活性升高。 PLD 催化磷脂酰胆碱水解生成脂质第二信使磷脂酸 (PA)。虽然 PA 信号传导的许多靶标已被确定，但癌细胞中 PA 最关键的靶标可能是 mTOR——雷帕霉素的哺乳动物靶标。 mTOR 广泛涉及抑制癌细胞凋亡程序的信号——通常称为生存信号。 mTOR 以两种多组分复合物的形式存在，称为 mTORC1 和 mTORC2。最近的数据表明，PA 是 mTORC1 和 mTORC2 复合物稳定性所必需的，因此也是 mTORC1 和 mTORC2 激酶活性所必需的。 PA 与 mTOR 的相互作用方式与雷帕霉素竞争，因此，PLD 活性升高会导致雷帕霉素耐药——这一点在涉及雷帕霉素策略的临床试验中很大程度上被忽视了。新兴肿瘤中发生的最早的基因变化通常是抑制默认的细胞凋亡程序，而这些程序可能代表了癌症的第一道防线。针对人类癌症的生存信号代表了一种合理的抗癌治疗策略。因此，了解调节 PA 水平的信号以及 PA 如何影响 mTOR 对于制定去抑制抑制细胞凋亡的生存信号的策略非常重要。这篇综述总结了 PA 在调节 mTOR 介导的促进癌细胞存活的信号中的作用。
During the past decade elevated phospholipase D (PLD) activity has been reported in virtually all cancers where it has been examined. PLD catalyzes the hydrolysis of phosphatidylcholine to generate the lipid second messenger phosphatidic acid (PA). While many targets of PA signaling have been identified, the most critical target of PA in cancer cells is likely to be mTOR – the mammalian target of rapamycin. mTOR has been widely implicated in signals that suppress apoptotic programs in cancer cells – frequently referred to as survival signals. mTOR exists as two multi-component complexes known as mTORC1 and mTORC2. Recent data has revealed that PA is required for the stability of both mTORC1 and mTORC2 complexes – and therefore also required for the kinase activity of both mTORC1 and mTORC2. PA interacts with mTOR in a manner that is competitive with rapamycin, and as a consequence, elevated PLD activity confers rapamycin resistance – a point that has been largely overlooked in clinical trials involving rapamycin-based strategies. The earliest genetic changes occurring in an emerging tumor are generally ones that suppress default apoptotic programs that likely represent the first line of defense of cancer. Targeting survival signals in human cancers represents a rational anti-cancer therapeutic strategy. Therefore, understanding the signals that regulate PA levels and how PA impacts upon mTOR could be important for developing strategies to de-repress the survival signals that suppress apoptosis. This review summarizes the role of PA in regulating the mTOR-mediated signals that promote cancer cell survival.
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DOI：
10.1158/1078-0432.ccr-08-0102
发表时间：
2008-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Garcia A;Zheng Y;Zhao C;Toschi A;Fan J;Shraibman N;Brown HA;Bar-Sagi D;Foster DA;Arbiser JL
通讯作者：
Arbiser JL
影响因子：
9.2
作者：
Fang, YM;Park, IH;Chen, J
通讯作者：
Chen, J
影响因子：
56.9
作者：
Fang, YM;Vilella-Bach, M;Chen, J
通讯作者：
Chen, J
影响因子：
4.8
作者：
Hui, L;Rodrik, V;Foster, DA
通讯作者：
Foster, DA
影响因子：
64.5
作者：
Jacinto, Estela;Facchinetti, Valeria;Su, Bing
通讯作者：
Su, Bing