Phospholipase D confers rapamycin resistance in human breast cancer cells
Phospholipase D confers rapamycin resistance in human breast cancer cells
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DOI：
10.1038/sj.onc.1206565
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发表时间：
2003-06-19
期刊：
影响因子：
8
通讯作者：
Foster, DA
中科院分区：
文献类型：
--
作者：
Chen, YH;Zheng, Y;Foster, DA
mTOR（mammalian target of rapamycin）是一种调节细胞周期进程和细胞生长的蛋白激酶。雷帕霉素是用于治疗乳腺癌和其他癌症的临床试验中的mTOR的高度特异性抑制剂。据报道，mTOR信号传导需要磷脂酸（PA），磷脂酶D（PLD）的代谢产物。PLD与mTOR一样，参与生存信号传导和细胞周期进程的调节。PLD活性在乳腺癌中经常升高。我们研究了雷帕霉素对具有不同水平PLD活性的乳腺癌细胞系的影响。PLD活性水平相对较低的MCF-7细胞对雷帕霉素的生长抑制作用高度敏感，而PLD活性比MCF-7细胞高10倍的MDA-MB-231细胞对雷帕霉素高度耐药。升高MCF-7细胞中PLD活性导致雷帕霉素抗性;并且抑制MDA-MB-231细胞中PLD活性增加雷帕霉素敏感性。升高的PLD活性在MCF-7细胞中也引起雷帕霉素抗性的S6激酶磷酸化和血清诱导的Myc表达。这些数据表明mTOR是PLD产生的生存信号的关键靶点，并表明乳腺癌中PLD水平可能是雷帕霉素治疗可能疗效的有价值指标。
mTOR (mammalian target of rapamycin) is a protein kinase that regulates cell cycle progression and cell growth. Rapamycin is a highly specific inhibitor of mTOR in clinical trials for the treatment of breast and other cancers. mTOR signaling was reported to require phosphatidic acid (PA), the metabolic product of phospholipase D (PLD). PLD, like mTOR, has been implicated in survival signaling and the regulation of cell cycle progression. PLD activity is frequently elevated in breast cancer. We have investigated the effect of rapamycin on breast cancer cell lines with different levels of PLD activity. MCF-7 cells, with relatively low levels of PLD activity, were highly sensitive to the growth-arresting effects of rapamycin, whereas MDA-MB-231 cells, with a 10-fold higher PLD activity than MCF-7 cells, were highly resistant to rapamycin. Elevating PLD activity in MCF-7 cells led to rapamycin resistance; and inhibition of PLD activity in MDA-MB-231 cells increased rapamycin sensitivity. Elevated PLD activity in MCF-7 cells also caused rapamycin resistance for S6 kinase phosphorylation and serum-induced Myc expression. These data implicate mTOR as a critical target for survival signals generated by PLD and suggest that PLD levels in breast cancer could be a valuable indicator of the likely efficacy of rapamycin treatment.