Survivin expression and cancer cell drug resistance

描述（由申请人提供）：Survivin是凋亡抑制剂（IAP）蛋白家族的新成员，在大多数正常成人组织中检测不到，但在癌症中高表达。据报道，紫杉醇介导的有丝分裂阻滞与survivin的诱导有关，survivin保留了癌细胞的存活途径。然而，我们的观察结果对这种模式提出了挑战。我们发现，紫杉醇诱导survivin是紫杉醇治疗后的早期事件，与紫杉醇介导的G2/M阻滞无关。此外，与早期时间点相比，增加紫杉醇治疗时间实际上减少了生存素诱导，即使G2/M细胞数量在这些时期增加。数据还显示，紫杉醇早期诱导survivin似乎与癌细胞对紫杉醇治疗的耐药性有关。废除

DESCRIPTION (provided by applicant): Survivin, a novel member of the inhibitor of apoptosis (IAP) protein family, is undetectable in most normal adult tissues but highly expressed in cancer. It has been reported that taxol-mediated mitotic arrest is associated with the induction of survivin, which preserves a survival pathway for cancer cells. However, we have made observations that challenge this paradigm. We have found that induction of survivin by taxol is an early event following taxol treatment and is independent of taxol-mediated G2/M arrest. Moreover, increasing treatment times with taxol actually reduces survivin induction in comparison with the early time-points even though the G2/M cell population increases over these periods. The data have also revealed that the early induction of survivin by taxol appears to be involved in cancer cell resistance to taxol treatment. Abrogation of this new survivin-associated survival pathway may provide the basis for novel approaches to eliminate cancer cells. In this proposal, we will use a number of cancer cell models to delineate the signaling pathways involved in taxol-mediated, cell cycle-independent induction of survivin and to explore the role and underlying mechanism of the rapid survivin induction by taxol in cancer cell drug resistance. Specifically, we will: 1) determine the effect of taxol on survivin induction and delineate the signaling pathways involved in taxol-mediated, cell cycle-independent survivin induction in different types of cancer cells; 2) examine the mechanistic role of taxol-mediated survivin induction in cancer cell survival; 3) evaluate the effects of inhibition of taxol-mediated survivin induction on taxol-induced cancer cell death; and 4) explore the transcriptional and post-transcriptional mechanism by which taxol upregulates survivin. These studies may extend the current understanding of the mechanisms of drug resistance and survivin action, and may reveal alternative therapeutic sites and/or targets to develop novel approaches for cancer treatment.