Hsp60 Regulation of Prostate Cancer Progression

Hsp60 对前列腺癌进展的调节

• 批准号: 10682487
• 负责人: Dhyan Chandra
• 金额: $ 37.71万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682487
• 关键词: Address; Androgens; Apoptosis; Attenuated; Caspase; Cell Nucleus; Cell Proliferation; Cell Survival; Cells; Chaperonin 60; Data; Data Analyses; Development; Disease; Generations; Genetic; Genetic Engineering; Gleason Grade for Prostate Cancer; Human; Hypoxia; Immune response; Inhibition of Apoptosis; Knock-out; Knockout Mice; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Mitochondria; Mitochondrial Proteins; Organoids; Patients; Primary Neoplasm; Production; Prognosis; Prostatic Neoplasms; Prostatic Tissue; Proteins; Reactive Oxygen Species; Regulation; Reporter; Research; Resistance; Resistance development; Role; Signal Transduction; Stress; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Uses; Treatment Efficacy; Tumor Burden; activating transcription factor; alternative treatment; androgen sensitive; cancer cell; cancer subtypes; castration resistant prostate cancer; chromatin immunoprecipitation; clinically relevant; docetaxel; enzalutamide; immunogenic cell death; in silico; in vivo; inhibitor; men; neoplastic cell; neuroendocrine phenotype; novel; novel therapeutics; overexpression; patient derived xenograft model; promoter; prostate cancer cell; prostate cancer progression; prostate carcinogenesis; proteostasis; response; standard of care; targeted treatment; therapy outcome; therapy resistant; transcription factor; tumor; tumor growth; tumor progression; tumorigenesis

Mitochondrial protein homeostasis (proteostasis) has been implicated in cancer and is regulated by mitochondrial unfolded protein response (UPRmt). However, it is unknown whether UPRmt promotes tumorigenesis and whether it could be targeted for therapeutic benefit in prostate cancer (PCa). This proposal will define how heat shock protein 60 (HSP60), a key component of UPRmt, promotes aggressive and resistant PCa. Using genetically-engineered triple knockout (TKO: deletion of Pten, Trp53, and Rb1) tumors, we observed that HSP60 is upregulated in aggressive tumors and castration-resistant prostate cancer (CRPC) compared to WT prostatic tissues. TCGA data analysis and our preliminary data using human PCa-specific TMAs demonstrated that HSP60 is upregulated in prostate tumors with higher Gleason Scores. HSP60-silencing induced caspase activation and inhibited cellular proliferation whereas HSP60 overexpression promoted cancer cell survival and proliferation. We provide the first evidence that, genetic deletion of HSP60 in TKO mouse and inhibition of HSP60 oligomerization by introducing HSP60D3G KI during prostate tumorigenesis, reduced tumor burden in vivo. We observed that activating transcription factor 5 (ATF5), specific for HSP60 expression and UPRmt activation, was upregulated with higher Gleason Scores, and ATF5 was translocated to nucleus during stress. Using in silico analysis, we have identified a novel UPRmt inhibitor (referred to as DCEM1), which induced robust apoptosis in PCa cells and blocked tumor growth in vivo. Based on these findings, we hypothesized that HSP60- dependent mitochondrial unfolded protein response promotes cancer cell adaptation during tumor progression and therapeutic resistance in PCa. Identification of UPRmt inhibitor provides alternative treatment option for patients with PCa. We propose the following Specific Aims to test this hypothesis. Aim 1. Define the role of transcription factor ATF5 in activating mitochondrial unfolded protein response. Aim 2: Evaluate whether HSP60 oligomerization maintains functional mitochondria and inhibits apoptosis to develop aggressive PCa. Aim 3. Explore the clinical relevance of HSP60 inhibition using patient-derived xenografts (PDXs) and primary tumor cells. Impact: The findings will provide fundamental understanding on how UPRmt is activated and how persistent mitochondrial stress is attenuated by UPRmt leading to development of aggressive and lethal PCa. Identification of unique UPRmt inhibitor represents a new therapeutic vulnerability in PCa that does not rely on androgen modulation. Therefore, UPRmt inhibition by DCEM1 will have greater therapeutic benefits for patients with androgen-dependent and androgen-independent CRPC.

线粒体蛋白稳态(蛋白稳态)与癌症和 受线粒体未折叠蛋白反应(UPRmt)调控。然而，目前还不清楚 UPRmt促进肿瘤发生及其是否可作为治疗前列腺癌的靶点 癌症(PCA)。这项提案将定义热休克蛋白60(HSP60)，它是 UPRmt，促进积极和抵抗的PCA。使用基因工程的三重敲除(TKO： Pten、Trp53和Rb1)肿瘤中，我们观察到HSP60在侵袭性肿瘤中表达上调 肿瘤和去势抵抗前列腺癌(CRPC)与WT前列腺癌组织的比较。TCGA 数据分析和我们使用人PCA特异性TMA的初步数据表明，HSP60 在Gleason评分较高的前列腺癌中表达上调。HSP60沉默诱导的半胱氨酸天冬氨酸酶 HSP60过表达促进癌细胞增殖 生存和繁殖。我们首次提供证据表明，TKO中HSP60的基因缺失 小鼠前列腺期导入HSP60D3GKI抑制HSP60寡聚 肿瘤的发生，减轻了体内的肿瘤负担。我们观察到激活转录因子5 (ATF5)是HSP60表达和UPRmt激活的特异性基因，随着Gleason的升高而上调 在应激过程中，ATF5移位到细胞核。在电子计算机分析中，我们有 发现了一种新的UPRmt抑制剂(称为DCEM1)，它可以诱导PCa细胞的强烈凋亡 细胞，并阻断体内肿瘤生长。基于这些发现，我们假设HSP60- 依赖线粒体未折叠蛋白反应促进癌细胞适应 前列腺癌的肿瘤进展和治疗耐药。UPRmt抑制剂的鉴定提供 前列腺癌患者的替代治疗选择。我们提出了以下具体目标来测试 这个假说。 目的1.明确转录因子ATF5在激活线粒体未折叠蛋白中的作用 回应。目的2：评估HSP60寡聚是否维持功能性线粒体和 抑制细胞凋亡，发展侵袭性前列腺癌。目的3.探讨热休克蛋白60的临床意义 使用患者来源的异种移植(PDX)和原代肿瘤细胞进行抑制。 影响：这些发现将提供关于UPRmt如何激活和 UPRmt如何减弱持续的线粒体应激导致侵袭性 和致命的前列腺癌。独特的UPRmt抑制剂的发现代表了一种新的治疗脆弱性 不依赖雄激素调节的前列腺癌。因此，DCEM1对UPRmt的抑制将具有 雄激素依赖和雄激素非依赖性患者的更大治疗效益 CRPC。