Cisplatin and taxol activate different signal pathways regulating cellular injury-induced expression of GADD153.
Signal transduction pathways activated by injury play a central role in coordinating the cellular responses that determine whether a cell survives or dies. GADD153 expression increases markedly in response to some types of cellular injury and the product of this gene causes cell cycle arrest. Using induction of GADD153 as a model, we have investigated the activation of the cellular injury response after treatment with taxol and cisplatin (cDDP). Activation of the GADD153 promoter coupled to the luciferase gene and transfected into human ovarian carcinoma 2008 cells correlated well with the increase in endogenous GADD153 mRNA after treatment with taxol but not after treatment with cDDP. Following treatment with cDDP, the increase in endogenous GADD153 mRNA was 10-fold greater than the increase in GADD153 promoter activity. Likewise, at equitoxic levels of exposure (IC80), cDDP produced a 5-fold greater increase in endogenous GADD153 mRNA than taxol. The tyrosine kinase inhibitor tyrophostin B46 had no significant effect on the ability of taxol to activate the GADD153 promoter, but inhibited activation of the GADD153 promoter by cDDP in a concentration-dependent manner. Tyrphostin B46 synergistically enhanced the cytotoxicity of cisplatin; however, the same exposure had no significant effect on the cytotoxicity of taxol. We conclude that (1) taxol and cDDP activate GADD153 promoter activity through different mechanisms; (2) the signal transduction pathway mediating induction by cDDP involves a tyrosine kinase inhibitable by tyrphostin B46; and (3) that inhibition of this signal transduction pathway by tyrphostin synergistically enhances cDDP toxicity.
Gately
D P
DP
Department of Biomedical Sciences, University of California, San Diego, La Jolla 92093-0812, USA.
Sharma
A
A
Christen
R D
RD
Howell
S B
SB
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000494:pharmacology; D022762:CCAAT-Enhancer-Binding Proteins; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009570:Nitriles / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects; D020032:Tyrphostins
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001597:Benzylidene Compounds; D022762:CCAAT-Enhancer-Binding Proteins; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009570:Nitriles; D012333:RNA, Messenger; D014157:Transcription Factors; D020032:Tyrphostins; C095713:alpha-cyano-(3,4-dihydroxy)-N-(3-phenylpropyl)cinnamide; D051742:Transcription Factor CHOP; D017239:Paclitaxel; D002945:Cisplatin