LY294002, an inhibitor of PI-3K, enhances heat sensitivity independently of p53 status in human lung cancer cells.
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.
Ohnishi
Ken
K
Department of Biology, Nara Medical University School of Medicine, Kashihara, Nara 634-8521, Japan.
Yasumoto
Jun-Ichi
J
Takahashi
Akihisa
A
Ohnishi
Takeo
T
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000628:therapy; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018832:Molecular Chaperones; D009025:Morpholines / Q000494:pharmacology*; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D000077022:Survivin; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D002867:Chromones; D004247:DNA; D004268:DNA-Binding Proteins; D055551:HSP27 Heat-Shock Proteins; D050884:HSP72 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D018832:Molecular Chaperones; D009025:Morpholines; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D000077022:Survivin; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C107489:BIRC5 protein, human; C057725:HSPB1 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one