Up-regulation of hTERT expression by low-dose cisplatin contributes to chemotherapy resistance in human hepatocellular cancer cells.
The telomerase is specifically activated in most malignant tumors but is usually inactive in normal somatic cells. It has been reported that telomerase has an anti-apoptotic role and up-regulation of telomerase helps cancer cells to be resistant to chemotherapeutic agent-induced cell death. The effect of cisplatin on telomerase activity is complex, and the exact mechanism remains largely unknown. In this study, we found that cisplatin activated telomerase activity and human telomerase reverse transcriptase (hTERT) expression in SMMC7721 human hepatocellular carcinoma cell line. Low-dose cisplatin up-regulated hTERT and NF-kappaB p65 expression and increased telomerase and NF-kappaB activity. Inhibition of NF-kappaB attenuated the hTERT expression and telomerase activity exposed to cisplatin, suggesting that NF-kappaB is responsible for the cisplatin-induced activation of the hTERT. Furthermore, preincubation of low-dose cisplatin which induced high expression of hTERT help hepatocellular carcinoma SMMC7721 cells survive under the high concentration of anti-cancer drugs. Inhibition of hTERT increased sensitivity of SMMC7721 cells to chemotherapy. Taken together, these results suggested that up-regulation of hTERT expression by low-dose cisplatin is NF-kappaB-dependent and contributes to chemotherapy resistance in human hepatocellular cancer cells.
Guo
Xian-Ling
XL
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, PR China.
Ma
Nan-Nan
NN
Zhou
Fei-Guo
FG
Zhang
Li
L
Bu
Xin-Xin
XX
Sun
Kai
K
Song
Jian-Rui
JR
Li
Rong
R
Zhang
Bai-He
BH
Wu
Meng-Chao
MC
Wei
Li-Xin
LX
D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D016328:NF-kappa B / Q000502:physiology; D019098:Telomerase / Q000032:analysis / Q000235:genetics*; D015854:Up-Regulation
D000970:Antineoplastic Agents; D016328:NF-kappa B; C509186:TERT protein, human; D019098:Telomerase; D002945:Cisplatin