Unravel a novel metabolic pathway orchestrating prostate cancer progression and therapeutic resistance

揭示协调前列腺癌进展和治疗耐药的新代谢途径

• 批准号: 10374340
• 负责人: Hui-Kuan Lin
• 金额: $ 49.74万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-03 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10374340
• 关键词: AKT Signaling Pathway; Ablation; Androgens; Automobile Driving; Back; Biochemical; Biochemical Genetics; Biological Assay; Cancer Etiology; Cancer Patient; Cell Maintenance; Cell Proliferation; Cell Survival; Cells; Cessation of life; Defect; Development; Drug resistance; Genetic; Goals; Human; Impairment; Inositol; Lead; Light; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Metabolic Pathway; Mitochondria; Neoplasm Metastasis; Oncogenic; Outcome; Pathologic; Patients; Pharmacology; Phosphotransferases; Physiological; Play; Population; Prostate; Prostate Ablation; Prostate Cancer therapy; Proteins; RNA Splicing; Regulation; Reporting; Resistance; Role; Signal Pathway; Signal Transduction; Solid; Specimen; Stem Cell Factor; Testing; Therapeutic; United States; Validation; Variant; Xenograft Model; advanced prostate cancer; aldehyde dehydrogenases; androgen deprivation therapy; assay development; base; cancer drug resistance; cancer stem cell; castration resistant prostate cancer; clinically relevant; clinically significant; druggable target; experimental study; genetic approach; in vivo; innovation; insight; knock-down; men; metabolomics; mouse model; new therapeutic target; novel; overexpression; patient derived xenograft model; prostate cancer cell; prostate cancer progression; resistance mechanism; stem cell biomarkers; stem cell population; stemness; survival outcome; therapeutic target; therapy resistant; transcriptomics; tumor; tumor metabolism

Summary Prostate cancer is the second leading cause of cancer deaths in the United States. While androgen ablation therapy (ABT) is the mainstay of therapy for men with prostate cancer, most patients with prostate cancer will inevitably develop castration-resistant prostate cancer (CRPC), which no longer responds to ABT treatment. Thus, understanding of the mechanisms leading to CRPC and ABT resistance is urgently needed. Several mechanisms account for the occurrence of CRPC, such as activation of 3-kinase/Akt signaling pathway, which plays a critical role in cell proliferation and cell survival, and higher expression of AR and AR splicing variants, which facilitate prostate cancer cell survival under very low androgen concentrations. Of note is that prostate cancer stem cells (PCSCs) also known as cancer initiating cells (CICs), which account for a small cell population prostate cancer cells, are critically involved in the development of CRPC. But how PCSCs are regulated and how they can be pharmacologically targeted are currently not well understood. While several stem cell factors such as SOX2 playing an important role in maintaining PCSC pool and functions are identified, there is no effective strategy to block the action of these proteins in order to eradicate PCSCs within the cancer. Thus, identifying key druggable targets maintaining PCSCs could provide novel paradigms and effective strategies for prostate cancer therapy and overcoming ABT resistance. Our goal in this study is to identify a novel mechanism underlying PCSC maintenance, which could be harnessed to develop an effective strategy for CRPC targeting. Using systematic metabolomics and transcriptomics in conjunction with biochemical validation and in vivo tumor development assays, we unraveled a novel oncogenic and metabolic signaling pathway, which was elevated during ABT treatment and in advanced human prostate cancer, is critical for maintaining the stemness and pool of PCSCs and CRPC development. Of note, we observed aberrant AMPK activation and AMPK-dependent mitochondria fission upon loss of this metabolic signaling, correlated with the defect in stemness and pool of PCSCs and prostate cancer progression. In light of these findings, we hypothesized that this newly discovered metabolic signaling is crucial for restricting aberrant AMPK-dependent mitochondrial fission to maintain the pool and stemness of PCSCs, thereby leading to CRPC and ABT resistance. Our hypothesis has been formulated based on our solid and innovative preliminary results. In this proposal, we proposed three specific aims to test this paradigm-shift hypothesis. Our study has not only revolutionized and significantly advanced our understanding of cancer metabolism in PCSC regulation, but also offered a promising strategy to treat advanced prostate cancer and overcoming ABT resistance.

摘要 前列腺癌是美国癌症死亡的第二大原因。当雄激素消融时 治疗(ABT)是男性前列腺癌的主要治疗方法，大多数前列腺癌患者将 不可避免地会患上耐去势前列腺癌(CRPC)，这种癌症对ABT治疗不再有效。 因此，迫切需要了解导致CRPC和ABT耐药的机制。几个 CRPC的发生有多种机制，如激活3-K/Akt信号通路， 在细胞增殖和细胞存活中起关键作用，AR和AR剪接变异体的高表达， 这有助于前列腺癌细胞在非常低的雄激素浓度下存活。值得注意的是，前列腺 癌症干细胞(PCSCs)也被称为癌症起始细胞(CICs)，它只占很小的细胞群 前列腺癌的发生、发展与前列腺癌的发生密切相关。但PCSC是如何受到监管的，以及 它们如何在药理上成为靶点目前还不太清楚。而几种干细胞因子 如SOX2在维持PCSC池中发挥的重要作用和功能是确定的，没有 有效的策略，以阻断这些蛋白质的行动，以消除癌症内的PCSCs。因此， 识别维持PCSCs的关键药物靶点可以提供新的范例和有效的战略 前列腺癌治疗和克服ABT耐药性。我们在这项研究中的目标是确定一种新的机制 基础PCSC维护，可以利用这一点来制定CRPC目标的有效战略。 使用系统代谢组学和转录组学结合生化验证和体内肿瘤 发展分析，我们揭开了一条新的致癌和代谢信号通路，它是上调的 在ABT治疗期间和在晚期人类前列腺癌中，是维持干细胞和池的关键 关于PCSC和CRPC开发的问题。值得注意的是，我们观察到AMPK的异常激活和AMPK依赖 线粒体在失去这一代谢信号时发生分裂，与茎和池的缺陷有关 PCSCs与前列腺癌进展。根据这些发现，我们假设这一新发现 代谢信号对限制依赖AMPK的异常线粒体分裂以维持池至关重要 和PCSCs的茎，从而导致对CRPC和ABT的抗性。我们的假设已经公式化了 基于我们扎实和创新的初步成果。在这个提案中，我们提出了三个具体目标来测试 这种范式转换假说。我们的研究不仅使我们的 了解癌症代谢在PCSC调控中的作用，也为晚期癌症的治疗提供了一种有前途的策略 前列腺癌和克服ABT耐药性。