Survivin as a predictor of cis-diamminedichloroplatinum sensitivity in gastric cancer patients.
Survivin, a member of the inhibitor-of-apoptosis family, inhibits apoptosis by blocking caspase-3 and -7 activation. Gastric cancer, which is among the most intractable of malignant tumors, is known for resistance to various drugs, including cis-diamminedichloroplatinum (CDDP). Since this agent induces apoptosis via caspase-3 activation, survivin may mediate the drug resistance. We investigated survivin messenger RNA (mRNA) expression in gastric cancers and the relationship between expression and sensitivity to CDDP. Expression of the survivin gene was significantly up-regulated in gastric cancers compared to the tissues of normal mucosa, atrophic gastritis, and intestinal metaplasia (P < 0.0001) as assessed by a quantitative reverse transcription-polymerase chain reaction (RT-PCR), and was negatively associated with overall survival of patients who received CDDP-based chemotherapy. To investigate whether survivin is a resistance factor against CDDP-induced apoptosis, we transfected wild-type and dominant-negative mutants of the survivin gene into gastric cancer cells using a lipofection method. Overexpression of survivin protected MKN45 cells from CDDP-induced apoptosis. Expression of the dominant-negative mutant of the survivin gene sensitized NUGC-3 cells to drug-induced apoptosis. These results indicate that survivin may be pivotal in the development of gastric cancer and resistance to CDDP, and therefore controlling expression of the survivin gene may be therapeutically useful.
Nakamura
Masashi
M
Department of Clinical Laboratory Medicine, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo 060-8543, Japan.
Tsuji
Naoki
N
Asanuma
Koichi
K
Kobayashi
Daisuke
D
Yagihashi
Atsuhito
A
Hirata
Koichi
K
Torigoe
Toshihiko
T
Sato
Noriyuki
N
Watanabe
Naoki
N
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000401:mortality; D000077022:Survivin; D014162:Transfection; D015854:Up-Regulation
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D002945:Cisplatin