Mitochondrial Heat Shock Protein 90 as a Novel Target for Radiation Resistant Prostate Cancer Treatment

线粒体热休克蛋白 90 作为抗辐射前列腺癌治疗的新靶点

• 批准号: 10119761
• 负责人: Luksana Chaiswing
• 金额: $ 32.1万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10119761
• 关键词: Adjuvant; Antibiotics; Azithromycin; Biological Models; Cancer Center; Cell Survival; Cells; Cessation of life; Event; FDA approved; Genetic Transcription; Goals; Heat-Shock Proteins 90; Imaging Techniques; Investigation; Kentucky; Link; Macrolides; Malignant neoplasm of prostate; Metabolism; Mitochondria; Molecular; Molecular Chaperones; Normal Cell; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Procedures; Prostate Cancer therapy; Prostatic Neoplasms; Proteins; Radiation; Radiation Tolerance; Radiation therapy; Radiation-Sensitizing Agents; Reactive Oxygen Species; Resistance; Resistance development; Safety; Testing; Translating; Universities; cancer cell; cancer recurrence; cancer therapy; clinical practice; improved; metabolomics; mitochondrial metabolism; novel; precision medicine; prostate cancer cell; radiation resistance; radioresistant; tumor; tumor metabolism

Radiation therapy is widely used to treat localized prostate tumors. However, cancer cells often develop resistance to radiation through unknown mechanisms and pose an intractable challenge. Radiation resistance is highly unpredictable, rendering the treatment less effective in many patients and frequently resulting in cancer recurrence. There is a dire need to uncover the molecular events that cause cells to become resistant in order to improve radiation therapy. In our in-depth investigations of radiation-resistant prostate cancer (RR-PCa), we found that mitochondrial heat shock protein 90 (mtHsp90) level and mitochondrial metabolism were aberrantly high when compared to radiosensitive PCa. mtHsp90 is a chaperone that maintains the stability of many diverse proteins, including those that are necessary for tumor survival and metabolism. We further demonstrated that decreasing mtHsp90 protein level significantly restored the sensitivity of RR-PCa cells to radiation. Hence, our overarching hypothesis is that mtHsp90 defines resistance of prostate cancer cells to radiation, a premise that will be put under stringent testing in this proposal. Reactive oxygen species (ROS) are known to reduce the level of mtHsp90 by interfering with its transcriptional and post-translational levels. We screened 768 FDA-approved drugs in search of a potent drug that could raise the level of ROS, but not be toxic to normal cells. We found Azithromycin (AZM), a macrolide antibiotic, to be the most effective drug that selectively increases mitochondrial ROS and reduces mtHsp90 protein level. We further demonstrated that AZM enhances the death of cancer cells with radiation treatment. Encouraged by robust results, we aim to advance our findings in this project, test our hypotheses, and develop a paradigm for adjuvant treatment that will ultimately enhance radiation therapy as a more effective procedure. The goals are: Aim 1, to determine the functional importance of mtHsp90 in RR-PCa cell survival and adaptive metabolisms, Aim 2, to determine mechanistically how ROS down-regulates mtHsp90 protein level and sensitizes RR-PCa, and Aim 3, to validate in preclinical models if AZM-generated ROS down-regulates mtHsp90 and enhances radiation treatment. The results will establish a novel link between mtHsp90 and RR-PCa. This study using state-of-the art metabolomics, imaging techniques, and model systems and has the potential to be translated into a clinical practice because AZM already has a good safety record. In the era of precision medicine, we are confident of the prospects of our closely-focused studies, which will push boundaries and make radiation therapy a better procedure, and our approach will set a precedent for many cancer treatments where radiation therapy is preferred.

放射治疗被广泛用于治疗局部前列腺肿瘤。然而，癌细胞通常通过未知的机制产生对辐射的抵抗力，并构成了棘手的挑战。耐药性是高度不可预测的，使许多患者的治疗效率较低，并且经常导致癌症复发。迫切需要发现会导致细胞变得抗性以改善放射治疗的分子事件。在对抗辐射前列腺癌（RR-PCA）的深入研究中，我们发现线粒体热休克蛋白90（MTHSP90）水平（MTHSP90）水平和线粒体代谢与放射性PCA相比异常高。 MTHSP90是维持许多多种蛋白质的稳定性，包括肿瘤生存和代谢所必需的蛋白质的稳定性。我们进一步证明，降低MTHSP90蛋白水平可以显着恢复RR-PCA细胞对辐射的敏感性。因此，我们的总体假设是MTHSP90定义了前列腺癌细胞对辐射的抗性，这一前提将在该提案中进行严格的测试。已知活性氧（ROS）通过干扰其转录和翻译后水平来降低MTHSP90的水平。我们筛选了768种FDA批准的药物，以寻找一种有效的药物，该药物可能会提高ROS水平，但对正常细胞不毒性。我们发现Azithromycin（AZM）是一种大环内酯类抗生素，是最有效的药物，可有效地增加线粒体ROS并降低MTHSP90蛋白水平。我们进一步证明，通过放射治疗，AZM增强了癌细胞的死亡。在强大的结果的鼓励下，我们旨在推进我们的发现，检验我们的假设，并开发用于辅助治疗的范式，最终将增强放射疗法作为更有效的程序。目标是：目标1，以确定MTHSP90在RR-PCA细胞存活和适应性代谢中的功能重要性，目标2，以机械的方式确定ROS如何下调MTHSP90蛋白水平并敏感RR-PCA并敏感RR-PCA，并将目标3降低，并在临床上对AZM生成的ros ross rad-SpsSp90降低了验证，以验证MTHSP90。结果将在MTHSP90和RR-PCA之间建立新的联系。这项研究使用最先进的代谢组学，成像技术和模型系统，并且有可能转化为临床实践，因为AZM已经具有良好的安全记录。在精确医学的时代，我们对我们密切关注的研究的前景充满信心，这将推动边界并使放射疗法成为更好的程序，而我们的方法将为许多优先放射治疗的癌症疗法树立先例。