Ohnishi Ken, Yasumoto Jun-Ichi, Takahashi Akihisa, Ohnishi Takeo
Department of Biology, Nara Medical University School of Medicine, Kashihara, Nara 634-8521, Japan.
Int J Oncol. 2006 Jul;29(1):249-53.
The aim of this study was to ascertain whether LY294002, an inhibitor of PI-3K, enhances heat sensitivity in human cancer cells regardless of their p53 status. Colony formation assays showed that LY294002 enhanced heat sensitivity in two human lung cancer cell lines; H1299/wild-type p53 (wtp53) and H1299/mutated p53 (mp53) cells. These cell lines have identical genetic backgrounds except for their p53 status. LY294002 suppressed the heat-induced accumulation of heat shock protein 27 (hsp27) and heat shock protein 72 (hsp72) in these cell lines. Heat-induced apoptosis was observed more frequently in H1299/wtp53 cells than in H1299/mp53 cells, and was enhanced by LY294002 in both cell lines. In addition, both the heat-induced phosphorylation of Akt and the accumulation of survivin were suppressed by LY294002. These results suggest that LY294002 inhibits anti-apoptosis signaling through hsp27 and hsp72 as well as cell survival signaling through Akt and survivin. LY294002 appears to be an attractive candidate for a p53-independent heat sensitizer in hyperthermic cancer therapy.
本研究的目的是确定PI-3K抑制剂LY294002是否能增强人癌细胞的热敏感性，而不论其p53状态如何。集落形成试验表明，LY294002增强了两种人肺癌细胞系的热敏感性；H1299/野生型p53（wtp53）和H1299/突变型p53（mp53）细胞。除了p53状态外，这些细胞系具有相同的遗传背景。LY294002抑制了这些细胞系中热诱导的热休克蛋白27（hsp27）和热休克蛋白72（hsp72）的积累。热诱导的凋亡在H1299/wtp53细胞中比在H1299/mp53细胞中更频繁地观察到，并且在两种细胞系中均被LY294002增强。此外，LY294002抑制了热诱导的Akt磷酸化和survivin的积累。这些结果表明，LY294002通过hsp27和hsp72抑制抗凋亡信号传导，以及通过Akt和survivin抑制细胞存活信号传导。LY294002似乎是热疗癌症中一种不依赖p53的热增敏剂的有吸引力的候选物。
