Survivin expression and cancer cell drug resistance

Survivin表达与癌细胞耐药性

基本信息

批准号：
7392643
负责人：
Fengzhi Li
金额：
$ 23.7万
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 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7392643
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（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是无法检测到的，但在癌症中高度表达。据报道，紫杉醇介导的有丝分裂停滞与Survivin的诱导有关，后者保留了癌细胞的生存途径。但是，我们进行了观察，挑战了这一范式。我们发现，紫杉醇是紫杉醇治疗后的早期事件，与紫杉醇介导的G2/m逮捕无关。此外，与早期时间点相比，使用紫杉醇的治疗时间实际上会降低幸存的诱导，即使在这些时期内G2/M细胞群增加。数据还表明，紫杉醇早期诱导紫杉醇的诱导剂似乎参与了癌细胞对紫杉醇治疗的耐药性。废除在这种新的生存相关的生存途径中，可以为消除癌细胞的新方法提供基础。在此提案中，我们将使用许多癌细胞模型来描述紫杉醇介导的，与细胞周期无关诱导的信号传导途径，并探索紫杉醇在癌细胞耐药性中迅速诱导紫杉醇迅速诱导的作用和潜在机制。具体而言，我们将：1）确定紫杉醇对Survivin诱导的影响，并描绘出紫杉醇介导的，与细胞周期无关的Survivin诱导中不同类型的癌细胞中所涉及的信号传导途径； 2）检查紫杉醇介导的Survivin诱导在癌细胞存活中的机理作用； 3）评估抑制紫杉醇介导的Survivin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Survivin的转录和转录后机制。这些研究可能会扩展对耐药性和遗传作用机制的当前理解，并可能揭示替代性治疗部位和/或靶标，以开发新的癌症治疗方法。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prostate-derived Ets transcription factor as a favorable prognostic marker in ovarian cancer patients.

DOI：
10.1002/ijc.23667
发表时间：
2008-09-15
期刊：
INTERNATIONAL JOURNAL OF CANCER
影响因子：
6.4
作者：
Ghadersohi, Ali;Odunsi, Kunle;Zhang, Shaozeng;Azrak, Rami G.;Bundy, Brian N.;Manjili, Masoud H.;Li, Fengzhi
通讯作者：
Li, Fengzhi

Cancer cell sensitivity to bortezomib is associated with survivin expression and p53 status but not cancer cell types.