Survivin expression and cancer cell drug resistance

描述（由申请人提供）：存活素是凋亡抑制剂（IAP）蛋白家族的新成员，在大多数正常成人组织中检测不到，但在癌症中高度表达。据报道，紫杉醇介导的有丝分裂阻滞与存活素的诱导有关，存活素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。我们已经发现，诱导生存素的紫杉醇治疗后的早期事件，是独立的紫杉醇介导的G2/M期阻滞。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存活素诱导，即使G2/M细胞群体在这些时期增加。这些数据还显示，紫杉醇对存活素的早期诱导似乎与癌细胞对紫杉醇治疗的耐药性有关。废除 这种新的生存素相关的生存途径的研究可能为消除癌细胞的新方法提供基础。在本研究中，我们将利用多种肿瘤细胞模型来描述紫杉醇介导的、不依赖于细胞周期的Survivin诱导的信号通路，并探讨紫杉醇快速诱导Survivin在肿瘤细胞耐药中的作用及其机制。具体而言，我们将：1）确定紫杉醇对存活素诱导的作用，并描绘不同类型癌细胞中紫杉醇介导的、细胞周期非依赖性的存活素诱导所涉及的信号通路; 2）检查紫杉醇介导的存活素诱导在癌细胞存活中的机制作用; 3）评估抑制紫杉醇介导的存活素诱导对紫杉醇诱导的癌细胞死亡的作用;（4）探讨紫杉醇上调survivin的转录和转录后机制。这些研究可能扩展目前对耐药性和生存素作用机制的理解，并可能揭示替代治疗位点和/或靶点，以开发癌症治疗的新方法。

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.