Escape of U251 glioma cells from temozolomide-induced senescence was modulated by CDK1/survivin signaling.

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.