Pycr1, pyrroline-5-carboxylate reductase 1, is the final enzyme in proline biosynthesis, converting pyrroline-5-carboxylate (P5C) to proline. Proline is crucial for maintaining cell redox balance and preventing apoptosis. PYCR1 has been associated with multiple cellular pathways and is of great biological importance, especially in cancer development. Mouse genetic models, such as knockout (KO) models, have been valuable for studying its function [9].

In cancer research, Pycr1 has been found to play oncogenic roles. In colorectal cancer, nuclear IGF1R phosphorylates PYCR1 at Tyrosine 135 under hypoxia, promoting its binding to ELK4 and recruitment to ELK4-targeted gene promoters, thus sustaining tumor growth [1]. In liver cancer, PYCR1 promotes cell growth and metastasis by regulating IRS1 expression through lactylation modification [2]. In breast cancer, cancer-associated fibroblasts (CAFs) require PYCR1-mediated proline synthesis for the deposition of pro-tumorigenic extracellular matrix [3]. In pancreatic, bladder, papillary renal cell, and lung cancers, knockdown of Pycr1 inhibits cell proliferation, invasion, and tumor growth in vivo and in vitro, suggesting its potential as a therapeutic target [4,5,7,8]. In allergic asthma, Pycr1 knockout in mice reduces proline levels in lung tissues, alleviating airway remodeling and EMT by modulating multiple signaling pathways [6].

In conclusion, Pycr1 is essential for proline biosynthesis and has significant impacts on various biological processes, especially in cancer and allergic asthma. The use of Pycr1 KO mouse models has revealed its oncogenic role in multiple cancers, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Zheng, Ke, Sha, Nannan, Hou, Guofang, Jiang, Yuhui, Chen, Tao. 2023. IGF1R-phosphorylated PYCR1 facilitates ELK4 transcriptional activity and sustains tumor growth under hypoxia. In Nature communications, 14, 6117. doi:10.1038/s41467-023-41658-z. https://pubmed.ncbi.nlm.nih.gov/37777542/

2. Wang, Haoyu, Xu, Mu, Zhang, Tong, Wang, Qian, Li, John Zhong. . PYCR1 promotes liver cancer cell growth and metastasis by regulating IRS1 expression through lactylation modification. In Clinical and translational medicine, 14, e70045. doi:10.1002/ctm2.70045. https://pubmed.ncbi.nlm.nih.gov/39422696/

3. Kay, Emily J, Paterson, Karla, Riera-Domingo, Carla, Zagnoni, Michele, Zanivan, Sara. 2022. Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. In Nature metabolism, 4, 693-710. doi:10.1038/s42255-022-00582-0. https://pubmed.ncbi.nlm.nih.gov/35760868/

4. Wang, Huanyu, Mao, Weilin, Lou, Wenhui, Xu, Xuefeng, Zhang, Lei. 2022. PYCR1: A Potential Prognostic Biomarker in Pancreatic Ductal Adenocarcinoma. In Journal of Cancer, 13, 1501-1511. doi:10.7150/jca.61498. https://pubmed.ncbi.nlm.nih.gov/35371311/

5. Du, Shuangkuan, Sui, Yongjie, Ren, Wei, Zhou, Jiancheng, Du, Chun. 2021. PYCR1 promotes bladder cancer by affecting the Akt/Wnt/β-catenin signaling. In Journal of bioenergetics and biomembranes, 53, 247-258. doi:10.1007/s10863-021-09887-3. https://pubmed.ncbi.nlm.nih.gov/33689096/

6. Xu, Tingting, Wu, Zhenzhen, Yuan, Qi, Huang, Mao, Ji, Ningfei. 2023. Proline is increased in allergic asthma and promotes airway remodeling. In JCI insight, 8, . doi:10.1172/jci.insight.167395. https://pubmed.ncbi.nlm.nih.gov/37432745/

7. Wang, Qiu-Li, Liu, Ling. 2019. PYCR1 is Associated with Papillary Renal Cell Carcinoma Progression. In Open medicine (Warsaw, Poland), 14, 586-592. doi:10.1515/med-2019-0066. https://pubmed.ncbi.nlm.nih.gov/31428683/

8. Zhang, Lihong, Zhao, Xinyu, Wang, Enqin, Xu, Hongkun, Zhang, Baojun. 2023. PYCR1 promotes the malignant progression of lung cancer through the JAK-STAT3 signaling pathway via PRODH-dependent glutamine synthesize. In Translational oncology, 32, 101667. doi:10.1016/j.tranon.2023.101667. https://pubmed.ncbi.nlm.nih.gov/37018868/

9. Stum, Morgane G, Tadenev, Abigail L D, Seburn, Kevin L, John, Simon W M, Burgess, Robert W. . Genetic analysis of Pycr1 and Pycr2 in mice. In Genetics, 218, . doi:10.1093/genetics/iyab048. https://pubmed.ncbi.nlm.nih.gov/33734376/