Characterizing and targeting PRMT5 in autophagy for cancer treatment

表征和靶向 PRMT5 在自噬中的癌症治疗

• 批准号: 10581891
• 负责人: Wenjian Gan
• 金额: $ 34.54万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581891
• 关键词: American; Arginine; Autophagocytosis; Biological Process; Biology; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cancer Etiology; Cell Culture Techniques; Cell Proliferation; Cessation of life; Clinical Trials; Combined Modality Therapy; Cytoplasm; Cytoprotection; Data; Genetic; Invaded; Mediating; Methylation; Modeling; Molecular; Neoplasm Metastasis; Oncogenic; Organ; Prognosis; Protein-Arginine N-Methyltransferase; Regulation; Resistance; Resources; Role; Sampling; Stress; Survival Rate; TRAF6 gene; Testing; Ubiquitination; Woman; Xenograft procedure; anticancer research; breast cancer progression; cancer diagnosis; cancer subtypes; cancer therapy; combat; effective therapy; improved; inhibition of autophagy; inhibitor; mRNA Differential Displays; malignant breast neoplasm; migration; mouse model; new therapeutic target; novel; pharmacologic; phase II trial; preclinical study; protein activation; protein expression; protein function; targeted agent; therapeutic target; therapy resistant; triple-negative invasive breast carcinoma; tumor growth; ubiquitin-protein ligase

Abstract Breast cancer (BC) is the most diagnosed cancer and the second leading cause of cancer death in American women. Triple negative breast cancer (TNBC) accounts for 15% to 20% of all BC cases and has the worst prognosis and overall survival. Although many targeted agents are ongoing clinical trials, none have significantly improved the survival in TNBC patients. Thus, the identification of novel targets and effective strategies, including combination therapies, are urgent needed for TNBC patients. PRMT5 is emerging as a potential therapeutic target. Several PRMT5 inhibitors have been developed and are currently being evaluated in clinical trials, including a phase II trial for early-stage BC. Compared to other BC subtypes, TNBC displays the strongest PRMT5 expression. High PRMT5 expression is positively correlated with poorer survival rate in TNBC patients. Despite its association with TNBC progression, PRMT5 regulation and the molecular mechanisms by which PRMT5 promotes TNBC remain elusive. Moreover, TNBC cell lines display differential sensitivity or resistance to PRMT5 inhibitors, but the mechanisms have yet to be defined. Our preliminary studies demonstrate that: (1) PRMT5 is ubiquitinated by E3 ubiquitin ligase TRAF6, which is important for its activation and TNBC cell proliferation; (2) PRMT5 suppresses autophagy induction and catalyzes ULK1 arginine methylation; and (3) autophagy inhibition sensitizes TNBC cells to PRMT5 inhibitor. Based on these preliminary findings, we propose three aims to test our central hypothesis that TRAF6, PRMT5, and ULK1 form a novel axis to regulate autophagy and TNBC progression, and combination of PRMT5 and autophagy inhibitors is a potential strategy to combat TNBC. To validate our hypothesis, we propose three Aims. In Aim 1, we will define the mechanism through which TRAF6 regulates PRMT5 activation. In Aim 2, we will define the molecular function of PRMT5 in autophagy regulation by methylating ULK1. In Aim 3, we will evaluate the synergistic effect of PRMT5 and autophagy inhibitors in TNBC. We believe that our proposed studies will not only substantially advance current understanding of regulatory mechanism and biological function of PRMT5, but also provide a rationale for combination of PRMT5 and autophagy inhibitors to treat TNBC.

抽象的 乳腺癌 (BC) 是美国诊断最多的癌症，也是癌症死亡的第二大原因 女性。三阴性乳腺癌 (TNBC) 占所有 BC 病例的 15% 至 20%，且病情最严重 预后和总生存期。尽管许多靶向药物正在进行临床试验，但没有一个具有显着效果 提高了 TNBC 患者的生存率。因此，确定新的目标和有效的策略，包括 TNBC 患者迫切需要联合治疗。 PRMT5 正在成为一种潜在的治疗方法 目标。几种 PRMT5 抑制剂已经开发出来，目前正在临床试验中进行评估， 包括针对早期 BC 的 II 期试验。与其他 BC 亚型相比，TNBC 显示最强 PRMT5 表达。 PRMT5高表达与TNBC患者较差的生存率呈正相关。 尽管 PRMT5 与 TNBC 进展相关，但 PRMT5 的调节及其分子机制 PRMT5 推广的 TNBC 仍然难以捉摸。此外，TNBC 细胞系表现出不同的敏感性或耐药性 PRMT5 抑制剂，但其机制尚未明确。我们的初步研究表明：（1） PRMT5被E3泛素连接酶TRAF6泛素化，这对其激活和TNBC细胞很重要 增殖; (2) PRMT5抑制自噬诱导并催化ULK1精氨酸甲基化；和（3） 自噬抑制使 TNBC 细胞对 PRMT5 抑制剂敏感。根据这些初步调查结果，我们建议 三是检验我们的中心假设，即 TRAF6、PRMT5 和 ULK1 形成调节自噬的新轴 和 TNBC 进展，PRMT5 和自噬抑制剂的组合是对抗的潜在策略 TNBC。为了验证我们的假设，我们提出三个目标。在目标 1 中，我们将定义一种机制，通过该机制 TRAF6 调节 PRMT5 激活。在目标 2 中，我们将定义 PRMT5 在自噬中的分子功能 通过甲基化 ULK1 进行调节。在目标3中，我们将评估PRMT5和自噬的协同效应 TNBC 中的抑制剂。我们相信，我们提出的研究不仅将大大推进当前的 了解 PRMT5 的调控机制和生物学功能，也提供了理论依据 PRMT5 和自噬抑制剂联合治疗 TNBC。