Investigating the Proline Cycle as a Potential Cancer Therapy Target

修改后的项目摘要/摘要 脯氨酸的生物合成和分解代谢共享一个共同的中间体--1-吡咯烷-5-羧酸(Δ1-pyrroline-5-cixylate，P5C)，其酶促相互转化被称为“Pro循环”。分解代谢的第一个酶是Pro脱氢酶(PROH)，它催化依赖FAD的Pro氧化成P5C，而生物合成的最后一个酶是P5C还原酶(PYCR1)，它催化依赖NAD(P)H的P5C还原成Pro。PROSH和PYCR1一起形成了Pro循环，这是一个新的途径，影响了电子从细胞质中的NAD(P)H到线粒体中的ATP合成的净转移。最近的研究表明，转移性乳腺癌细胞改变了他们的新陈代谢，以利用脯氨酸循环来产生能量，这表明PROSH和PYCR1是潜在的癌症治疗靶点的假设。这一观点得到了体内数据的支持，该数据表明，在原位乳腺癌小鼠模型中，Pro类似物对PROHH的抑制会损害肺转移的形成。这些结果促使这个短期项目使用聚焦和高通量筛选方法开发针对PROSH和PYCR1的化学探针。即将开发的这套探针将使未来的研究能够机械地剖析Pro代谢在癌症进展中的作用，并评估Pro循环作为癌症治疗目标的可控性。我们希望这些知识将导致新的癌症治疗策略的长期发展。

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.