Investigating the Proline Cycle as a Potential Cancer Therapy Target

研究脯氨酸循环作为潜在的癌症治疗目标

基本信息

批准号：
10254225
负责人：
Donald F Becker
金额：
$ 34.96万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10254225
关键词：
ATP Synthesis Pathway Anabolism Animals Binding Biochemical Biophysics Breast Cancer Cell Breast Cancer Model Cancer Cell Growth Catabolism Cell Survival Cells Cellular Stress Cessation of life Chemicals Complex Cytoplasm Data Distant Electron Transport Enzymes Future Goals Growth Homeostasis Impairment International Aspects Knowledge Libraries Malignant Neoplasms Measures Metabolic Metabolic Pathway Metabolism Metastatic Neoplasm to the Lung Metastatic breast cancer Mitochondria Molecular Mechanisms of Action Neoplasm Metastasis Organ Oxidation-Reduction Pathway interactions Pharmaceutical Chemistry Play Production Proline Proline Dehydrogenase Protein Biosynthesis Research Role Signal Transduction Structure Techniques Therapeutic Intervention analog base cancer cell carboxylate cell growth cofactor enzyme activity enzyme biosynthesis high throughput screening in vivo inhibitor/antagonist macromolecule mouse model novel novel therapeutic intervention nucleotide metabolism oxidation pyrroline pyrroline 5 carboxylate reductase screening targeted cancer therapy targeted treatment therapeutic target tumor metabolism tumor progression

项目摘要

Modified Project Summary/Abstract Proline biosynthesis and catabolism share a common intermediate, Δ1-pyrroline-5-carboxylate (P5C), and the enzymatic interconversion of proline and P5C is known as the “proline cycle”. The first enzyme of catabolism, proline dehydrogenase (PRODH), catalyzes the FAD-dependent oxidation of proline to P5C, while the last enzyme of biosynthesis, P5C reductase (PYCR1), catalyzes the NAD(P)H-dependent reduction of P5C to proline. Together, PRODH and PYCR1 form the proline cycle, a novel pathway that effects the net transfer of electrons from NAD(P)H in the cytoplasm to the synthesis of ATP in mitochondria. Recent studies have shown that metastatic breast cancer cells alter their metabolism to harness the proline cycle for energy production, suggesting the hypothesis that PRODH and PYCR1 are potential cancer therapy targets. This idea is supported by in vivo data showing that the inhibition of PRODH by a proline analog impairs the formation of lung metastases in orthotopic mouse models of breast cancer. These results motivate this short-term project to develop chemical probes against PRODH and PYCR1 using focused and high-throughput screening approaches. The set of probes to be developed will enable future studies to mechanistically dissect the role of proline metabolism in cancer progression and assess the tractability of the proline cycle as a cancer therapy target. We expect that this knowledge will result in the long-term in new therapeutic strategies against cancer.

修改的项目摘要/摘要脯氨酸的生物合成和分解代谢具有共同的中间体Δ1-吡咯氨酸-5-羧酸盐（P5C），脯氨酸和P5C的酶促互动称为“脯氨酸循环”。分解代谢，脯氨酸脱氢酶（PODH）的第一种酶催化了脯氨酸的FAD依赖性氧化为P5C，而生物合成的最后一个酶，P5C还原（Pycr1）催化NAD（P）H依赖性P5C促蛋白的HAD（P）H依赖性。 prodh和pycr1共同形成了脯氨酸循环，这是一种新的途径，它会影响电子从细胞质中NAD（P）H的净转移到线粒体中ATP的合成。最近的研究表明，转移性乳腺癌细胞改变其代谢以利用脯氨酸的生产周期，这表明PODH和PYCR1是潜在的癌症治疗靶标的假设。体内数据支持了这一想法，表明脯氨酸模拟对PODH的抑制作用会损害乳腺癌的原位小鼠模型中肺转移的形成。这些结果激发了这个短期项目，以使用重点和高通量筛选方法来针对PODH和PYCR1进行化学问题。将要开发的一组问题将使未来的研究能够机械剖析脯氨酸代谢在癌症进展中的作用，并评估脯氨酸周期作为癌症治疗靶标的易干性。我们预计，这种知识将导致针对癌症的新治疗策略的长期。