Survivin expression and cancer cell drug resistance

描述(申请人提供)：Survivin是凋亡抑制蛋白(IAP)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停滞与Survivin的诱导有关，Survivin为癌细胞提供了一条生存途径。然而，我们的观察结果挑战了这一范式。我们发现紫杉醇诱导Survivin是紫杉醇治疗后的早期事件，并且独立于紫杉醇介导的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Survivin的诱导，即使在这些时间段G2/M细胞数量增加。数据还显示，紫杉醇对Survivin的早期诱导似乎与癌细胞对紫杉醇治疗的耐药性有关。废止 这一新的Survivin相关生存途径的研究可能为消除癌细胞的新方法提供基础。在这个方案中，我们将使用一些癌细胞模型来描述紫杉醇介导的、细胞周期非依赖性的Survivin诱导的信号通路，并探索紫杉醇快速诱导Survivin在癌细胞耐药中的作用和潜在机制。具体地说，我们将：1)确定紫杉醇对Survivin诱导的影响，并描述紫杉醇在不同类型癌细胞中诱导Survivin的信号通路；2)检测紫杉醇介导的Survivin诱导在癌细胞存活中的机制；3)评估紫杉醇介导的Survivin诱导抑制对紫杉醇诱导的癌细胞死亡的影响；以及4)探索紫杉醇上调Survivin的转录和转录后机制。这些研究可能扩展目前对耐药机制和Survivin作用机制的理解，并可能揭示替代治疗部位和/或靶点，以开发新的癌症治疗方法。

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.