Guo Xian-Ling, Ma Nan-Nan, Zhou Fei-Guo, Zhang Li, Bu Xin-Xin, Sun Kai, Song Jian-Rui, Li Rong, Zhang Bai-He, Wu Meng-Chao, Wei Li-Xin
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, PR China.
Oncol Rep. 2009 Sep;22(3):549-56. doi: 10.3892/or_00000470.
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.
端粒酶在大多数恶性肿瘤中被特异性激活，但在正常体细胞中通常无活性。据报道，端粒酶具有抗凋亡作用，端粒酶的上调有助于癌细胞抵抗化疗药物诱导的细胞死亡。顺铂对端粒酶活性的影响较为复杂，确切机制在很大程度上仍不清楚。在本研究中，我们发现顺铂可激活SMMC7721人肝癌细胞系中的端粒酶活性和人端粒酶逆转录酶（hTERT）表达。低剂量顺铂上调hTERT和NF-κB p65表达，并增加端粒酶和NF-κB活性。抑制NF-κB可减弱顺铂作用下的hTERT表达和端粒酶活性，提示NF-κB负责顺铂诱导的hTERT激活。此外，预先用诱导hTERT高表达的低剂量顺铂处理有助于肝癌SMMC7721细胞在高浓度抗癌药物作用下存活。抑制hTERT可增加SMMC7721细胞对化疗的敏感性。综上所述，这些结果表明低剂量顺铂上调hTERT表达是NF-κB依赖性的，并导致人肝癌细胞产生化疗耐药性。
