Honokiol suppresses survival signals mediated by Ras-dependent phospholipase D activity in human cancer cells.
Honokiol suppresses survival signals mediated by Ras-dependent phospholipase D activity in human cancer cells.
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DOI：
10.1158/1078-0432.ccr-08-0102
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发表时间：
2008-07-01
期刊：
影响因子：
--
通讯作者：
Arbiser JL
中科院分区：
文献类型：
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作者：
Garcia A;Zheng Y;Zhao C;Toschi A;Fan J;Shraibman N;Brown HA;Bar-Sagi D;Foster DA;Arbiser JL
磷脂酶D（PLD）活性升高在几种人类癌细胞系中提供存活信号，并在细胞受到血清撤回应激时抑制细胞凋亡。因此，靶向PLD存活信号具有抑制依赖PLD存活的癌细胞存活的潜力。和诺平是一种在小鼠模型中抑制肿瘤生长的化合物。本研究的目的是研究和厚朴酚对PLD存活信号的影响以及这些信号的Ras依赖性。在PLD活性提供存活信号的人癌细胞系中检测和诺明对PLD活性的影响。PLD生存信号对Ras的依赖性进行了研究，也研究了和厚朴对Ras激活的影响。我们在这里报告说，honoklatin抑制PLD活性在人类癌细胞中，PLD已被证明能抑制细胞凋亡。PLD活性通常响应于血清戒断的应激而升高，并且重要的是，应激诱导的PLD活性增加被和诺啡肽选择性地抑制。应激诱导的PLD活性增加伴随着Ras活化的增加，并且MDA-MB-231乳腺癌细胞中应激诱导的PLD活性增加依赖于Ras。PLD活性也依赖于GTP酶RalA和ADP核糖基化因子。重要的是，和诺啡肽抑制Ras激活。本文提供的数据表明，和诺明可能是一种有价值的治疗试剂，用于靶向大量依赖Ras和PLD生存的人类癌症。
Elevated phospholipase D (PLD) activity provides a survival signal in several human cancer cell lines and suppresses apoptosis when cells are subjected to the stress of serum withdrawal. Thus, targeting PLD survival signals has potential to suppress survival in cancer cells that depend on PLD for survival. Honokiol is a compound that suppresses tumor growth in mouse models. The purpose of this study was to investigate the effect of honokiol on PLD survival signals and the Ras dependence of these signals. The effect of honokiol upon PLD activity was examined in human cancer cell lines where PLD activity provides a survival signal. The dependence of PLD survival signals on Ras was investigated, as was the effect of honokiol on Ras activation. We report here that honokiol suppresses PLD activity in human cancer cells where PLD has been shown to suppress apoptosis. PLD activity is commonly elevated in response to the stress of serum withdrawal, and, importantly, the stress-induced increase in PLD activity is selectively suppressed by honokiol. The stress-induced increase in PLD activity was accompanied by increased Ras activation, and the stress-induced increase in PLD activity in MDA-MB-231 breast cancer cells was dependent on a Ras. The PLD activity was also dependent on the GTPases RalA and ADP ribosylation factor. Importantly, honokiol suppressed Ras activation. The data provided here indicate that honokiol may be a valuable therapeutic reagent for targeting a large number of human cancers that depend on Ras and PLD for their survival.