You Yongping, Geng Xiaozeng, Zhao Peng, Fu Zhen, Wang Cunzu, Chao Shengwu, Liu Ning, Lu Ailing, Gardner Kevin, Pu Peiyu, Kong Chunsheng, Ge Yun, Judge Susan I V, Li Qingdi Q
Department of Neurosurgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, P. R. China.
Cell Mol Life Sci. 2007 Mar;64(5):621-31. doi: 10.1007/s00018-007-6424-4.
Telomerase activation is a critical event in cell immortalization, and an increase in human telomerase reverse transcriptase (hTERT) expression is the key step in activating telomerase. The phosphatase and tensin homolog (PTEN) gene encodes a double-specific phosphatase that induces cell cycle arrest, inhibits cell growth, and causes apoptotic cell death. Here, we evaluated a combined PTEN and antisense hTERT gene therapy for experimental glioma in vitro and in vivo. We demonstrated that infection with antisense-hTERT and wild-type-PTEN adenoviruses significantly inhibited human U251 glioma cell proliferation in vitro and glioma growth in a xenograft mouse model. The efficacy of therapy was obviously higher in the tumor xenografts infected with both PTEN and antisense hTERT than in the gliomas infected with either agent alone at the same total viral dose. Consistent with these results, we showed that telomerase activity and hTERT protein levels were markedly reduced in the glioma cells following adenovirus infection. In contrast, the levels of PTEN protein expression were dramatically increased in these cells. Our data indicate that combination treatment with antisense hTERT and wild-type PTEN effectively suppresses the malignant growth of human glioma cells in vitro and in tumor xenografts, suggesting a promising new approach in glioma gene therapy that warrants further investigation.
端粒酶激活是细胞永生化过程中的关键事件，而人端粒酶逆转录酶（hTERT）表达的增加是激活端粒酶的关键步骤。磷酸酶和张力蛋白同源物（PTEN）基因编码一种双特异性磷酸酶，可诱导细胞周期停滞、抑制细胞生长并导致细胞凋亡性死亡。在此，我们评估了PTEN与反义hTERT基因联合疗法对体外和体内实验性胶质瘤的作用。我们证明，用反义hTERT和野生型PTEN腺病毒感染可显著抑制人U251胶质瘤细胞的体外增殖以及异种移植小鼠模型中的胶质瘤生长。在相同总病毒剂量下，PTEN和反义hTERT联合感染的肿瘤异种移植中，治疗效果明显高于单独感染任何一种药物的胶质瘤。与这些结果一致，我们发现腺病毒感染后胶质瘤细胞中的端粒酶活性和hTERT蛋白水平显著降低。相反，这些细胞中PTEN蛋白表达水平显著增加。我们的数据表明，反义hTERT与野生型PTEN联合治疗可有效抑制体外和肿瘤异种移植中人胶质瘤细胞的恶性生长，提示这是一种有前景的胶质瘤基因治疗新方法，值得进一步研究。
