The Role of Mortalin in Thyroid Cancer

Mortalin 在甲状腺癌中的作用

• 批准号: 10583210
• 负责人: Jong-In Park
• 金额: $ 43.63万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-10 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583210
• 关键词: ATP Citrate (pro-S)-Lyase; Acetyl Coenzyme A; Address; Bioenergetics; Biology; Cell Death Induction; Cell Line; Cell Proliferation; Cell Survival; Cessation of life; Characteristics; Citrates; Citric Acid Cycle; Collaborations; Common Neoplasm; DNA; Data; Data Set; Development; ERR1 protein; Enzymes; GRP75; Genetic Transcription; Genus Hippocampus; Glucose; Glycolysis; Glycolysis Inhibition; Goals; Heat-Shock Proteins 70; In Vitro; Isotopes; Maintenance; Malignant Neoplasms; Malignant neoplasm of thyroid; Mediating; Metabolic; Metabolic stress; Metabolism; Mitochondria; Molecular; Molecular Chaperones; NCOR1 gene; Oncogene Activation; Oncogenes; Oncogenic; Orphan; Oxidative Stress; Patients; Process; Production; Proliferating; Pyruvate; Pyruvate Kinase; Reactive Oxygen Species; Regulation; Research; Risk; Role; Signal Transduction; Stress; Testing; The Cancer Genome Atlas; Therapeutic; Translating; Tumor Cell Line; Tumor Subtype; Up-Regulation; Warburg Effect; cancer subtypes; cell transformation; clinical efficacy; efficacy evaluation; in vivo; inhibitor; knock-down; metabolome; mortalin; neoplastic cell; novel strategies; overexpression; patient derived xenograft model; promoter; stress tolerance; synergism; therapeutic target; thyroid neoplasm; transcription factor; transcriptome sequencing; tumor; tumor metabolism

The goal of this project is to elucidate the mechanism by which mortalin is upregulated in thyroid cancer, determine the role of mortalin for tumor cell metabolism, and evaluate the potential of the metabolic processes that mortalin regulates as a therapeutic target. Metabolic reprogramming in the processes of energy and building block production is critical for tumor development and maintenance, but is associated with the risk of a lethal metabolic stress. It is therefore conceivable that malignant tumor cells might have successfully developed a protective mechanism in this context. If identified, such a mechanism may be targeted to unleash a death signal in tumor cells. We previously demonstrated that depletion of mortalin (GRP75/HSPA9), a molecular chaperone in the HSP70 family, causes lethal bioenergetic and oxidative stress in tumor cells, proposing that mortalin upregulation is a mechanism to protect tumor cells from a metabolic stress. Current understanding of the role of mortalin and its regulation is very limited in thyroid cancer, which is a metabolically active tumor. Our analysis of the TCGA RNAseq dataset revealed that a thyroid cancer-specific correlation exists between mortalin and ESRRA, an orphan transcription factor that regulates metabolic reprogramming. In our preliminary study, ESRRA depletion downregulated mortalin expression and induced cell death in different thyroid tumor cell lines, while this lethality was substantially abrogated by mortalin overexpression. These data led us to hypothesize that ESRRA is a tumor type- specific transcription factor that mediates mortalin overexpression in thyroid cancer and that mortalin is necessary for ESRRA to regulate thyroid tumor cell metabolism. Our metabolome analysis suggests that mortalin knockdown markedly depletes acetyl-CoA and its precursors in the context of the reductive TCA cycle, while increasing lactate and glucose. Moreover, depletion of ATP-citrate lyase (ACL), the enzyme that synthesizes cytosolic acetyl-CoA from citrate produced through the reductive TCA cycle, induced similar lethal effects as mortalin depletion whereas overexpression of pyruvate kinase M2 (PKM2), the enzyme that produces pyruvate to often facilitate the Warburg effect, conferred tolerance to mortalin depletion. Based upon these data, we further hypothesize that mortalin regulates the interplay between the Warburg effect and the reductive TCA cycle to facilitate cytosolic acetyl-CoA production. By extension, we predict that ACL inhibition is a promising strategy to suppress mortalin-dependent thyroid tumor cells and can be effectively combined with glycolysis inhibition. To test these hypotheses, Aim 1 will determine how ESRRA regulates mortalin transcription and examine their correlated expression and functional relationship in different thyroid tumor subtypes. Aim 2 will determine how mortalin regulates the interplay between glycolysis and the reductive TCA cycle to facilitate cytosolic acetyl-CoA production. Aim 3 will determine whether ACL is an effective target to suppress mortalin-dependent thyroid tumor cells in vitro and in vivo.

该项目的目标是阐明 Mortalin 在甲状腺癌中上调的机制， 确定 Mortalin 对肿瘤细胞代谢的作用，并评估代谢的潜力 mortalin 作为治疗靶标调节的过程。代谢重编程过程 能量和构建模块的产生对于肿瘤的发展和维持至关重要，但与 具有致命代谢应激的风险。因此可以想象，恶性肿瘤细胞可能具有 在此背景下成功开发了保护机制。如果确定的话，这样的机制可能是 旨在释放肿瘤细胞的死亡信号。我们之前证明了 mortalin 的消耗 (GRP75/HSPA9) 是 HSP70 家族中的分子伴侣，可引起致命的生物能和氧化反应 肿瘤细胞中的应激，提出 Mortalin 上调是保护肿瘤细胞免受 代谢压力。目前对 Mortalin 在甲状腺中的作用及其调节的了解非常有限 癌症，这是一种代谢活跃的肿瘤。我们对 TCGA RNAseq 数据集的分析表明 mortalin 和 ESRRA 之间存在甲状腺癌特异性相关性，ESRRA 是一种孤儿转录因子， 调节代谢重编程。在我们的初步研究中，ESRRA 消耗下调了 mortalin 在不同的甲状腺肿瘤细胞系中表达并诱导细胞死亡，而这种致死率基本上是 因 mortalin 过度表达而被废除。这些数据使我们推测 ESRRA 是一种肿瘤类型 - 介导甲状腺癌中 mortalin 过度表达的特定转录因子，mortalin 是 ESRRA 调节甲状腺肿瘤细胞代谢所必需的。我们的代谢组分析表明 在还原 TCA 的背景下，mortalin 敲低显着耗尽乙酰辅酶 A 及其前体 循环，同时增加乳酸和葡萄糖。此外，ATP-柠檬酸裂解酶 (ACL) 的消耗，该酶 通过还原 TCA 循环产生的柠檬酸合成胞质乙酰辅酶 A，诱导 与 mortalin 耗竭相似的致死作用，而丙酮酸激酶 M2 (PKM2) 的过度表达， 产生丙酮酸的酶通常会促进瓦尔堡效应，赋予对致命灵的耐受性 消耗。基于这些数据，我们进一步假设 mortalin 调节 Warburg 效应和还原 TCA 循环促进胞质乙酰辅酶 A 的产生。推而广之，我们 预测 ACL 抑制是抑制致命素依赖性甲状腺肿瘤细胞的一种有前途的策略，并且 能有效地与糖酵解抑制相结合。为了检验这些假设，目标 1 将确定如何 ESRRA 调节 mortalin 转录并检查其相关表达和功能关系 在不同的甲状腺肿瘤亚型中。目标 2 将确定 mortalin 如何调节两者之间的相互作用 糖酵解和还原性 TCA 循环促进胞质乙酰辅酶 A 的产生。目标 3 将决定 ACL 是否是体外和体内抑制致命素依赖性甲状腺肿瘤细胞的有效靶点。