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Hsp60 regulation of apoptosis in prostate cancer

Hsp60 对前列腺癌细胞凋亡的调节

基本信息

批准号：
9691545
负责人：
Dhyan Chandra
金额：
$ 6.87万
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：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2018-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Heat shock protein 60 (Hsp60) is highly expressed in prostate cancer (PCa) and is associated with poor prognosis. Poor prognosis in patients results from defective apoptosis signaling. Defective apoptosis is due to high expression of Hsp60 in PCa cells, however, the underlying molecular mechanisms are not yet fully defined. Our goal is to determine how Hsp60 regulates PCa cell apoptosis. We and others observed that Hsp60 is localized to mitochondria in normal prostate epithelial cells, whereas in PCa cells Hsp60 is in both mitochondria and cytosol. We provided evidence that mitochondrial Hsp60 (mHsp60) promotes caspase-3 activation and thus induces apoptosis, whereas cytosolic Hsp60 (cHsp60) fails to support caspase-3 activation and suppresses apoptosis. The majority of mHsp60 exists as oligomers, whereas cHsp60 is in monomeric form. In addition, Hsp60-oligomer induces caspase-3 activation but Hsp60-monomer lacks this function. Therefore, whether Hsp60 promotes or suppresses apoptosis in response to anticancer agents is dependent upon both its localization and its molecular forms. Because majority of caspase-3 localizes in the cytosol and Hsp60-oligomer resides in mitochondria, we hypothesized that accumulation of Hsp60-oligomer in the cytosol induces efficient apoptosis. Further we propose that defining how mHsp60 activates caspase-3 in mitochondria has the potential to improve existing PCa therapy. To address the hypothesis and test possible therapeutic potentials, we will: Aim 1. Define the mechanisms of caspase-3 activation by mHsp60, and identify unknown mHsp60-/cHsp60-interacting proteins. The findings will delineate how oligomeric mHsp60 interacts with and activates caspase-3 in mitochondria, and how active caspase-3 in mitochondria amplifies the caspase cascade. Aim 2. Investigate the oligomerization status of Hsp60 and its impact on apoptosis. The goal of this Aim is to correlate the impact of caspase-3 activating function of Hsp60-oligomer in cancer and normal cells. Aim 3. Evaluate whether Hsp60-oligomer is a key determinant of apoptosis in PCa tumor. The completion of proposed research in this Aim may establish Hsp60-oligomer as a key target for PCa therapy. Important impact: The majority of caspase-3 resides in the cytosol, thus new anti-PCa agents that trigger/enhance oligomerization of cHsp60 and/or release of mHsp60 from mitochondria to the cytosol will induce efficient caspase-3 activation and apoptosis. Since monomeric cHsp60 is highly expressed in the cytosol of cancer and tumor cells but not in normal cells, anticancer agents that induce/enhance oligomerization of Hsp60 in the cytosol will selectively induce cancer cell apoptosis. Importantly, this proposal will identify Hsp60-oligomer as a new caspase-3-activating complex in apoptosis, and direct activation of caspase-3 by Hsp60 oligomer will be highly efficient means to induce PCa cell apoptosis because it does not rely on activation of initiator caspases (e.g., caspase-9, and -8).

描述（由申请人提供）：热休克蛋白60（Hsp 60）在前列腺癌（PCa）中高度表达，并与不良预后相关。患者的不良预后是由缺陷的凋亡信号传导引起的。前列腺癌细胞凋亡的缺陷是由于Hsp 60的高表达，然而，其潜在的分子机制尚未完全确定。我们的目标是确定热休克蛋白60如何调节前列腺癌细胞凋亡。我们和其他人观察到，Hsp 60定位于正常前列腺上皮细胞的线粒体，而在前列腺癌细胞中，Hsp 60既存在于线粒体中，也存在于胞浆中。我们提供的证据表明，线粒体Hsp 60（mHsp 60）促进caspase-3的激活，从而诱导细胞凋亡，而胞质Hsp 60（cHsp 60）未能支持caspase-3的激活和抑制细胞凋亡。大多数mHsp 60以寡聚体形式存在，而cHsp 60以单体形式存在。此外，Hsp 60-寡聚体诱导半胱天冬酶-3活化，但Hsp 60-单体缺乏这种功能。因此，Hsp 60是否促进或抑制细胞凋亡，以响应抗癌剂是依赖于它的定位和它的分子形式。由于大多数caspase-3定位于细胞质中，而Hsp 60-寡聚体位于线粒体中，因此我们假设Hsp 60-寡聚体在细胞质中的积累诱导有效的凋亡。此外，我们提出，确定mHsp 60如何激活线粒体中的caspase-3有可能改善现有的PCa治疗。为了解决假设和测试可能的治疗潜力，我们将：目的1。定义mHsp 60激活caspase-3的机制，并识别未知的mHsp 60/cHsp 60相互作用蛋白。这些发现将描述寡聚体mHsp 60如何与线粒体中的caspase-3相互作用并激活caspase-3，以及线粒体中的caspase-3如何放大caspase级联反应。目标二。探讨热休克蛋白60的寡聚化状态及其对细胞凋亡的影响。本研究的目的是将肿瘤细胞和正常细胞中Hsp 60-寡聚体的caspase-3激活功能的影响联系起来。目标3。评估Hsp 60寡聚体是否是PCa肿瘤细胞凋亡的关键决定因素。在这个目标中完成拟议的研究可能会建立Hsp 60寡聚体作为PCa治疗的关键靶点。重要影响：大部分半胱天冬酶-3存在于胞质溶胶中，因此触发/增强cHsp 60的寡聚化和/或mHsp 60从线粒体释放到胞质溶胶的新的抗PCa剂将诱导有效的半胱天冬酶-3活化和细胞凋亡。由于单体cHsp 60在癌和肿瘤细胞的胞质溶胶中高度表达，而在正常细胞中不表达，因此诱导/增强胞质溶胶中Hsp 60寡聚化的抗癌剂将选择性地诱导癌细胞凋亡。重要的是，该提议将鉴定Hsp 60-寡聚体作为凋亡中的新的半胱天冬酶-3-活化复合物，并且Hsp 60寡聚体直接活化半胱天冬酶-3将是诱导PCa细胞凋亡的高效手段，因为它不依赖于起始半胱天冬酶的活化（例如，半胱天冬酶-9和-8）。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transformations of the macromolecular landscape at mitochondria during DNA-damage-induced apoptotic cell death.

DOI：
10.1038/cddis.2014.405
发表时间：
2014-10-09
期刊：
Cell death & disease
影响因子：
9
作者：
Yadav N;Pliss A;Kuzmin A;Rapali P;Sun L;Prasad P;Chandra D
通讯作者：
Chandra D

A Single-Organelle Optical Omics Platform for Cell Science and Biomarker Discovery.

DOI：
10.1021/acs.analchem.1c01131
发表时间：
2021-06-15
期刊：
Analytical chemistry
影响因子：
7.4
作者：
Pliss A;Kuzmin AN;Lita A;Kumar R;Celiku O;Atilla-Gokcumen GE;Gokcumen O;Chandra D;Larion M;Prasad PN
通讯作者：
Prasad PN

Mitochondrial dysfunction-mediated apoptosis resistance associates with defective heat shock protein response in African-American men with prostate cancer.

DOI：
10.1038/bjc.2016.88
发表时间：
2016-05-10
期刊：
British journal of cancer
影响因子：
8.8
作者：
Chaudhary AK;Bhat TA;Kumar S;Kumar A;Kumar R;Underwood W;Koochekpour S;Shourideh M;Yadav N;Dhar S;Chandra D
通讯作者：
Chandra D

A potential role of X-linked inhibitor of apoptosis protein in mitochondrial membrane permeabilization and its implication in cancer therapy.