Bar J, Lukaschuk N, Zalcenstein A, Wilder S, Seger R, Oren M
The Chaim Sheba Medical Center, Department of Oncology, Tel Hashomer, Israel.
Cell Death Differ. 2005 Dec;12(12):1578-87. doi: 10.1038/sj.cdd.4401677. Epub 2005 Jun 3.
The p53 tumor suppressor plays a key role in the natural protection against cancer. Activation of p53 by DNA-damaging agents can contribute to successful elimination of cancer cells via chemotherapy-induced apoptosis. The phosphatidylinositol-3 kinase (PI3K) pathway, triggered in normal cells upon exposure to growth factors, regulates a cascade of proliferation and survival signals. The PI3K pathway is abnormally active in many cancers, thus making it an attractive target for inactivation in an attempt to achieve better cancer therapy. We report here that exposure to LY294002, a potent PI3K inhibitor, aborts the activation of p53 by several drugs commonly used in cancer chemotherapy. Concomitantly, LY294002 attenuates p53-dependent, chemotherapy-induced apoptosis of cancer cells. These findings invoke an unexpected positive role for PI3K in p53 activation by anticancer agents, and suggest that the efficacy of PI3K inhibitors in cancer therapy may be greatly affected by the tumor p53 status.
p53肿瘤抑制因子在癌症的天然防御中起着关键作用。DNA损伤剂激活p53可通过化疗诱导的凋亡促进癌细胞的成功清除。磷脂酰肌醇-3激酶（PI3K）通路在正常细胞暴露于生长因子时被触发，调节一系列增殖和存活信号。PI3K通路在许多癌症中异常活跃，因此使其成为试图实现更好癌症治疗而使其失活的有吸引力的靶点。我们在此报告，暴露于强效PI3K抑制剂LY294002会阻断几种癌症化疗常用药物对p53的激活。同时，LY294002减弱了p53依赖的、化疗诱导的癌细胞凋亡。这些发现揭示了PI3K在抗癌药物激活p53过程中出人意料的积极作用，并表明PI3K抑制剂在癌症治疗中的疗效可能会受到肿瘤p53状态的极大影响。
