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：
9887222
负责人：
Donald F Becker
金额：
$ 36.88万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9887222
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.

修改后的项目摘要/摘要脯氨酸生物合成和分解代谢有一个共同的中间体——Δ1-吡咯啉-5-羧酸酯（P5C），脯氨酸和P5C的酶促相互转化被称为“脯氨酸循环”，分解代谢的第一个酶是脯氨酸脱氢酶（PRODH）。脯氨酸依赖 FAD 氧化为 P5C，而生物合成的最后一个酶， P5C 还原酶 (PYCR1) 催化 NAD(P)H 依赖性 P5C 还原为脯氨酸，PRODH 和 PYCR1 共同形成脯氨酸循环，这是一种影响细胞质中 NAD(P)H 电子净转移的新途径。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循环产生能量，这表明 PRODH 和 PYCR1 是潜在癌症的假设。这一想法得到了体内数据的支持，该数据显示脯氨酸类似物抑制 PRODH 会损害乳腺癌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的开发针对 PRODH 和PYCR1 使用有针对性的高通量筛选方法，这组待开发的探针将使未来的研究能够从机制上剖析脯氨酸代谢在癌症进展中的作用，并评估脯氨酸循环作为一个过程的可处理性。我们期望这些知识将带来长期的癌症治疗新策略。