Song Zhenhua, Pan Yunyun, Ling Gengqiang, Wang Shiyong, Huang Min, Jiang Xiaodan, Ke Yiquan
Department of Neurosurgery, Zhujiang Hospital, Southern Medical UniversityGuangzhou 510282, China.
The National Key Clinic Specialty, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Southern Medical UniversityGuangzhou 510282, China.
Am J Transl Res. 2017 May 15;9(5):2163-2180. eCollection 2017.
Temozolomide (TMZ) has been widely used in conjunction with radiotherapy for treating various types of cancers. However, tumor cells arrested in senescence due to TMZ administration can sometimes escape and become drug resistant. In the current study, the possible role of survivin in the senescence escape of TMZ-treated glioma cells was comprehensively studied. The levels of survivin and CDK1 expression in a human glioma cell line (U251) were monitored, and cell apoptosis, cell cycle distribution, anchorage-independent growth, and senescence were studied in U251 cells in different degrees of senescence. To further investigate how survivin affects the TMZ-resistance of gliomas, we modulated the levels of survivin and CKD1 expression in TMZ-treated cells and then examined how the treated cells responded. The results showed that knockdown of the gene increased the sensitivity of glioma cells to TMZ treatment by inducing senescent cells to become apoptotic. Moreover, after senescence was induced, expression of the gene became suppressed, but survivin levels returned to normal after the cells had escaped from senescence. While down-regulation of the gene in senescent and senescence-escaping U251 cells had no effect on cell apoptosis, cell cycle distribution, or senescence status, it dramatically reduced the anchorage-independent growth ability of the cells. Additionally, CDK1 was able to not only enhance the anchorage-independent growth ability of the cells, but also contribute to their further senescence escape by modulating the survivin and other pathways. In conclusion, the gene was necessary for glioma cells to escape from and enter into senescence during treatment with TMZ.
替莫唑胺（TMZ）已广泛与放疗联合用于治疗各种类型的癌症。然而，因使用TMZ而停滞在衰老状态的肿瘤细胞有时会逃逸并产生耐药性。在当前研究中，全面研究了生存素在TMZ处理的胶质瘤细胞衰老逃逸中的可能作用。监测了人胶质瘤细胞系（U251）中生存素和细胞周期蛋白依赖性激酶1（CDK1）的表达水平，并研究了不同衰老程度的U251细胞中的细胞凋亡、细胞周期分布、非锚定依赖性生长和衰老情况。为了进一步研究生存素如何影响胶质瘤对TMZ的耐药性，我们调节了TMZ处理细胞中生存素和CDK1的表达水平，然后检测处理后的细胞如何反应。结果表明，该基因的敲低通过诱导衰老细胞凋亡增加了胶质瘤细胞对TMZ治疗的敏感性。此外，诱导衰老后该基因的表达受到抑制，但细胞从衰老中逃逸后生存素水平恢复正常。虽然在衰老和衰老逃逸的U251细胞中下调该基因对细胞凋亡、细胞周期分布或衰老状态没有影响，但它显著降低了细胞的非锚定依赖性生长能力。此外，CDK1不仅能够增强细胞的非锚定依赖性生长能力，还通过调节生存素和其他途径促进细胞进一步从衰老中逃逸。总之，该基因是胶质瘤细胞在TMZ治疗期间从衰老中逃逸并进入衰老所必需的。
