Downregulation of XIAP expression induces apoptosis and enhances chemotherapeutic sensitivity in human gastric cancer cells.
X-linked inhibitor of apoptosis (XIAP) is the most potent member of the inhibitor of apoptosis protein (IAP) gene family in terms of its ability to inhibit caspases and suppress apoptosis. Recent evidence has suggested that XIAP is a key determinant in chemoresistance of cancer cells. To explore a novel approach for ameliorating chemotherapy of gastric cancer, the antisense expression vector for the XIAP gene was constructed and transferred into gastric cancer cell lines, MKN-45 (wild-type p53) and MKN-28 (mutant-type p53). This transfer resulted in significant downregulation of XIAP expression, decreased in vitro cell viabilities, and induced apoptosis. In transferred cells, inactive caspase-3 precursors were cleaved into the active subunits (p20 and p17) during apoptosis induced by downregulation of XIAP. The inhibitory effects of cisplatin and mitomycin C on the growth of XIAP downregulated cancer cells were significantly enhanced. In addition, this process occurred only in wild-type p53 (MKN-45), but not in mutant-type p53 (MKN-28) gastric cancer cells. The data presented suggest that downregulation of XIAP via antisense RNA can lead to apoptosis of gastric cancer cells in vitro, correlating with cellular p53 status and activation of caspase-3. This finding could lead to a potential strategy for improving the efficiency of therapies for gastric cancer.
Tong
Qiang-Song
QS
Department of Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China. qs_tong@hotmail.com
Zheng
Li-Duan
LD
Wang
Liang
L
Zeng
Fu-Qing
FQ
Chen
Fang-Min
FM
Dong
Ji-Hua
JH
Lu
Gong-Cheng
GC
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D053148:Caspase 3; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D003131:Combined Modality Therapy; D016373:DNA, Antisense / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005822:Genetic Vectors; D006801:Humans; D016685:Mitomycin / Q000627:therapeutic use; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000188:drug therapy*; D051636:X-Linked Inhibitor of Apoptosis Protein
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D016373:DNA, Antisense; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D016685:Mitomycin; C505407:CASP3 protein, human; D053148:Caspase 3; D002945:Cisplatin