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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.

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