Possible involvement of persistent activity of the mammalian target of rapamycin pathway in the cisplatin resistance of AFP-producing gastric cancer cells.
AFP-producing gastric carcinoma (AFPGC) is a highly malignant variant of gastric cancer. An effective chemotherapy is needed to improve on the poor outcome of this disease. Survival signals activated by intracellular kinase networks could be involved in chemoresistance in malignant tumors. We investigated the role of a pivotal kinase pathway, the mammalian target of rapamycin complex 1 (mTORC1) pathway, in the effectiveness of chemotherapeutic agents in three AFPGC cell lines (GCIY, FU97 and Takigawa) as well as in four cell lines of conventional-type gastric carcinoma (CGC). AFPGC cells were generally resistant to multiple chemotherapeutic agents, including cisplatin, while CGC cells were generally sensitive. Downstream targets of mTORC1, including p70S6K and 4EBP1, were phosphorylated in all cell lines. Interestingly, cisplatin virtually abolished phosphorylation of p70S6K and 4EBP1 in CGC cells, while phosphorylation was maintained in cisplatin-treated AFPGC cells. The addition of rapamycin, an inhibitor of mTORC1, diminished the remaining activity of mTORC1 and significantly intensified the cytotoxic action of cisplatin in AFPGC cells. These results suggested that persistent activity of mTORC1 signals in cisplatin-treated AFPGC cells is involved in the mechanisms of cisplatin resistance in AFPGC. Finally, combined treatment of rapamycin and cisplatin significantly suppressed the subcutaneously implanted GCIY cells. In conclusion rapamycin may be a potential supplemental agent for the treatment of AFPGC when used in combination with cisplatin.
Kamata
Shigeyuki
S
Department of Molecular Pathology, Chiba University Graduate School of Medicine, Chiba, Japan.
Kishimoto
Takashi
T
Kobayashi
Soichi
S
Miyazaki
Masaru
M
Ishikura
Hiroshi
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011494:Protein Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000502:physiology; D023041:Xenograft Model Antitumor Assays; D000509:alpha-Fetoproteins / Q000096:biosynthesis*; D051028:bcl-2-Associated X Protein / Q000032:analysis
D000970:Antineoplastic Agents; C500984:CRTC1 protein, human; D014157:Transcription Factors; D000509:alpha-Fetoproteins; D051028:bcl-2-Associated X Protein; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin; D020123:Sirolimus