Survivin expression and cancer cell drug resistance

Survivin表达与癌细胞耐药性

基本信息

批准号：
7231471
负责人：
Fengzhi Li
金额：
$ 23.44万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7231471
关键词：
Adult Apoptosis Apoptosis Inhibitor BIRC4 gene Breast Cancer Cell CDKN1A gene Cancer cell line Caspase Caspase Inhibitor Cell Cycle Cell Death Cell Line Cell Survival Cell model Cells Data Development Drug resistance Epidermal Growth Factor Receptor Estrogen Receptors Event Fluorouracil G2/M Arrest Immunotherapy Individual Inhibition of Apoptosis Investigation Lead M cell MCF7 cell Malignant Neoplasms Mediating Microtubule stabilizing agent Mitosis Mitotic Molecular Molecular Target Mutation Numbers P-Glycoprotein P-Glycoproteins Paclitaxel Pathway interactions Penetrance Phosphorylation Phosphotransferases Population Post-Transcriptional Regulation Principal Investigator Protein Family Regulation Reporting Resistance Role Signal Pathway Site Small Interfering RNA Stimulus Therapeutic Time Tissues Tubulin Up-Regulation base cancer cell cancer therapy caspase-2 caspase-3 caspase-9 cell type chemotherapeutic agent cisplatin/etoposide protocol inhibitor-of-apoptosis protein inhibitor/antagonist irradiation member neoplastic cell novel novel strategies oncoprotein p21 programs promoter survivin treatment duration

项目摘要

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.

描述（申请人提供）：生存素是凋亡抑制剂（IAP）蛋白家族的新成员，在大多数正常成人组织中检测不到，但在癌症中高表达。据报道，紫杉醇介导的有丝分裂停滞与生存素的诱导有关，生存素保留了癌细胞的生存途径。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生存素是紫杉醇治疗后的早期事件，并且与紫杉醇介导的G2/M停滞无关。此外，与早期时间点相比，增加紫杉醇的治疗时间实际上减少了存活素诱导，尽管 G2/M 细胞群在这些时期有所增加。数据还显示，紫杉醇对生存素的早期诱导似乎与癌细胞对紫杉醇治疗的抵抗有关。废除这种新的生存素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。在本提案中，我们将利用多种癌细胞模型来描绘紫杉醇介导的、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在癌细胞药物中的作用和潜在机制。反抗。具体来说，我们将：1）确定紫杉醇对生存素诱导的影响，并描绘不同类型癌细胞中紫杉醇介导的、不依赖于细胞周期的生存素诱导所涉及的信号通路； 2) 检查紫杉醇介导的生存素诱导在癌细胞存活中的机制作用； 3)评价抑制紫杉醇介导的生存素诱导对紫杉醇诱导的癌细胞死亡的影响； 4）探索紫杉醇上调生存素的转录和转录后机制。这些研究可能会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/或靶标，以开发癌症治疗的新方法。