Functional Investigation of the Mitochondrial Pyruvate Carrier in Prostate Cancer

前列腺癌线粒体丙酮酸载体的功能研究

• 批准号: 9232100
• 负责人: David Alan Bader
• 金额: $ 3.85万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232100
• 关键词: Androgen Receptor; Basic Science; Binding; Cell Proliferation; Citrates; Clinical; Communication; Comprehension; Data; Development; Disease; Disease-Free Survival; Enzymes; Experimental Designs; Fellowship; Gene Targeting; Genetic; Glucose; Goals; Growth; Hormones; In Vitro; Investigation; Link; Lipids; Literature; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Measurement; Measures; Mediating; Mediator of activation protein; Mentorship; Metabolic; Methods; Mitochondria; Modification; Mus; Normal tissue morphology; Nude Mice; Oncogenic; Oncologist; Outcome; Pattern; Pharmacology; Property; Prostatic Neoplasms; Pyruvate; Refractory; Research; Research Training; Resistance; Role; Testing; Therapeutic; Translational Research; Transplantation; United States National Institutes of Health; Xenograft procedure; base; cancer cell; career; career development; cohort; design; drug development; human imaging; improved; in vivo; in vivo imaging; inhibitor/antagonist; innovation; interest; lipid biosynthesis; migration; neoplastic cell; novel therapeutics; prostate cancer cell; public health relevance; pyruvate carrier; skills; therapy development; trafficking; translational impact; tumor; tumor growth; tumor metabolism; tumor progression; uptake; virtual

 DESCRIPTION (provided by applicant): Androgen receptor (AR)-induced de-novo lipid synthesis enables the growth and survival of hormone sensitive and castrate-resistant prostate cancer cells, but the metabolic alterations mediated by AR to support lipogenesis in prostate cancer are poorly understood. Lipogenesis requires pyruvate to generate lipid precursors (e.g. citrate) and recent in-vivo imaging strategies have demonstrated that, in contrast to virtually all other tumors, prostate tumors take up pyruvate more rapidly and reliably than glucose. Further, a subunit of the mitochondrial pyruvate carrier (MPC), MPC2, is a direct AR target gene, suggesting a link between AR action pyruvate trafficking, and lipogenesis. The long-term goal of this project is the identification, characterization, and targeted disruption of critical mediatorsof prostate cancer metabolism. The overall objective of the current proposal is to determine the mechanism by which AR alters pyruvate trafficking to fuel lipogenesis in prostate cancer. The overarching central hypothesis is that AR regulates the MPC to increase pyruvate flux into mitochondria to enable oncogenic growth by increasing lipogenic capacity of tumor cells. The rationale of this proposal is that characterization of the mechanism underlying increased pyruvate trafficking in prostate cancer will likely enable the development of strategies to therapeutically manipulate pyruvate flux. Such treatments could be applied to both hormone sensitive and treatment refractory castrate-resistant prostate cancer. In order to accomplish the overall objective, the central hypothesis will be tested by pursuing the following three specific aims: 1) Determine the impact of altered MPC subunit expression on pyruvate flux by experimentally modifying MPC subunit composition and measuring a variety of metabolic endpoints in addition to using mass-spectroscopy-based methods to perform 13C pyruvate tracing. 2) Define MPC-dependent tumor properties using in-vitro measurements of tumor cell proliferation, invasive capacity, and lipogenic capacity. 3) Assess the impact of MPC perturbation on prostate tumor growth in-vivo by transplanting nude mice with prostate cancer cells harboring stable modifications to MPC subunit expression or treating xenografted mice with the MPC inhibitor UK5099. Regarding outcomes, completion of the research plan will define the metabolic and oncogenic consequences of the altered MPC subunit expression pattern observed in prostate cancer. The significance of this contribution derives from the expected translational opportunities made possible by the characterization of lipogenic substrate trafficking in prostate cancer, disruption of which represents a rational therapeutic strategy in al stages of the disease. The proposed research is innovative because it focuses on understanding and disrupting tumor-specific metabolic substrate trafficking rather than enzymatic activities common to normal tissues and tumor cells alike. It is expected this expansion of focus to include substrate trafficking will broaden the approach to metabolic targeting in cancer while opening new research horizons in drug development.

 描述（由申请人提供）：雄激素受体（AR）诱导的从头脂质合成使激素敏感性和去势抵抗性前列腺癌细胞能够生长和存活，但对AR介导的支持前列腺癌中脂肪生成的代谢改变知之甚少。脂肪生成需要丙酮酸盐来生成脂质前体（例如柠檬酸盐），并且最近的体内成像策略已经证明，与几乎所有的 其他肿瘤，前列腺肿瘤比葡萄糖更快更可靠地摄取丙酮酸。此外，线粒体丙酮酸载体（MPC）的亚基MPC2是直接AR靶基因，表明AR作用丙酮酸运输和脂肪生成之间的联系。该项目的长期目标是识别、表征和靶向破坏前列腺癌代谢的关键介质。目前的建议的总体目标是确定AR改变丙酮酸运输以促进前列腺癌脂肪生成的机制。首要的中心假设是AR调节MPC以增加丙酮酸流入线粒体，从而通过增加肿瘤细胞的脂肪生成能力来实现致癌生长。该建议的基本原理是，表征前列腺癌中丙酮酸运输增加的潜在机制可能会使治疗操纵丙酮酸流量的策略得以发展。这种治疗可以应用于激素敏感性和治疗难治性去势抵抗性前列腺癌。为了实现总体目标，将通过追求以下三个具体目标来测试中心假设：1）除了使用基于质谱的方法进行13 C丙酮酸追踪之外，还通过实验性地改变MPC亚基组成并测量各种代谢终点来确定改变的MPC亚基表达对丙酮酸通量的影响。2)使用肿瘤细胞增殖、侵袭能力和脂肪生成能力的体外测量来定义MPC依赖性肿瘤特性。3)通过移植具有MPC亚基表达稳定修饰的前列腺癌细胞的裸鼠或用MPC抑制剂UK5099治疗异种移植小鼠，评估MPC扰动对体内前列腺肿瘤生长的影响。关于结果，研究计划的完成将确定在前列腺癌中观察到的改变的MPC亚基表达模式的代谢和致癌后果。这一贡献的重要性来自于通过表征前列腺癌中的脂肪生成底物运输而可能实现的预期翻译机会，其破坏代表了疾病所有阶段的合理治疗策略。这项研究是创新的，因为它专注于理解和破坏肿瘤特异性代谢底物的运输，而不是正常组织和肿瘤细胞共同的酶活性。预计这种将重点扩展到包括底物运输的方法将拓宽癌症代谢靶向的方法，同时为药物开发开辟新的研究视野。

项目成果

The Landscape of microRNA Targeting in Prostate Cancer Defined by AGO-PAR-CLIP.

• DOI: 10.1016/j.neo.2016.04.008
• 发表时间: 2016-06
• 期刊: Neoplasia (New York, N.Y.)
• 作者: Hamilton MP;Rajapakshe KI;Bader DA;Cerne JZ;Smith EA;Coarfa C;Hartig SM;McGuire SE
• 通讯作者: McGuire SE