Pycr1, or pyrroline-5-carboxylate reductase 1, is a key enzyme in proline biosynthesis, catalyzing the final step of converting pyrroline-5-carboxylate (P5C) to proline [9]. Proline metabolism is involved in multiple cellular processes, and Pycr1 has been associated with maintaining redox balance and preventing apoptosis [10]. Mouse models have been crucial in understanding its function.

In various cancers, Pycr1 has been shown to play oncogenic roles. In colorectal cancer, under hypoxia, nuclear IGF1R phosphorylates Pycr1 at Tyrosine 135, promoting its binding to ELK4 and subsequent recruitment to ELK4-targeted genes' promoters, which sustains tumor growth [1]. In breast cancer, cancer-associated fibroblasts (CAFs) rely on Pycr1-mediated proline synthesis for the deposition of pro-tumorigenic extracellular matrix. Reducing Pycr1 levels in CAFs decreased tumour collagen production, growth, and metastatic spread [2]. In liver, bladder, pancreatic, papillary renal cell, and lung cancers, knockdown or inhibition of Pycr1 led to decreased cell proliferation, invasion, and metastasis, and increased apoptosis, often through affecting signaling pathways like Akt/Wnt/β-catenin, PI3K/AKT/mTOR, and JAK-STAT3 [3,4,6,7,8]. In allergic asthma, Pycr1 knockout in a murine model decreased proline in lung tissues, reducing airway remodeling and epithelial-mesenchymal transition (EMT) [5].

In conclusion, Pycr1 is essential for proline biosynthesis and has significant impacts on various biological processes. Studies using gene knockout models in mice have revealed its oncogenic role in multiple cancers and its contribution to airway remodeling in allergic asthma, 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. 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/

3. 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/

4. 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/

5. 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/

6. 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/

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/

10. Milne, Kirsty, Sun, Jianhui, Zaal, Esther A, Jamieson, Craig, Agami, Reuven. 2019. A fragment-like approach to PYCR1 inhibition. In Bioorganic & medicinal chemistry letters, 29, 2626-2631. doi:10.1016/j.bmcl.2019.07.047. https://pubmed.ncbi.nlm.nih.gov/31362921/