Abstract
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.