PRODH, also known as proline dehydrogenase or proline oxidase (PRODH/POX), is a mitochondria-localized enzyme that catalyzes proline degradation [3,4,5]. It is involved in proline metabolism, a pathway relevant to various biological processes. Proline metabolism is associated with tumor metabolism reprogramming, mitochondrial oxidative phosphorylation regulation, and apoptosis regulation, highlighting its overall biological importance [1,2,3]. Genetic models such as gene knockout (KO) mouse models can be valuable for studying its functions.

In breast cancer cells, PRODH expression is reduced in tamoxifen-resistant cells. Overexpression of PRODH enhances tamoxifen response in vitro and in vivo, while knockdown confers tamoxifen resistance. Mechanistically, ferroptosis is inhibited in tamoxifen-resistant cells, and PRODH overexpression restores it [1]. In naive human embryonic stem cells (hESCs), PRODH knockdown promotes mitochondrial oxidative phosphorylation (mtOXPHOS) and reactive oxygen species (ROS) production, triggering autophagy, DNA damage, and apoptosis. This shows that PRODH safeguards naive pluripotency by limiting mtOXPHOS and ROS production [2]. In the heart, cardiac-specific PRODH knockout mice exhibit worsened cardiac dysfunction after transverse aortic constriction (TAC), while overexpression mice show a protective effect. PRODH overexpression in cardiomyocytes redirects proline catabolism to replenish tricarboxylic acid cycle intermediates, enhance energy production, and restore glutathione redox balance during pressure-overload-induced cardiac remodeling [6].

In conclusion, PRODH plays essential roles in regulating tamoxifen resistance in breast cancer through ferroptosis, safeguarding naive pluripotency in hESCs by controlling mitochondrial function, and modulating cardiac remodeling during pressure overload. Studies using KO or overexpression mouse models have significantly contributed to understanding its roles in these disease-related biological processes.

References:

1. Zhang, Ping, Qian, Na, Lai, Haigen, Liu, Mengqi, Cui, Jiajun. 2024. PRODH Regulates Tamoxifen Resistance through Ferroptosis in Breast Cancer Cells. In Genes, 15, . doi:10.3390/genes15101316. https://pubmed.ncbi.nlm.nih.gov/39457440/

2. Chen, Cheng, Liu, Qianyu, Chen, Wenjie, Huang, Liming, Wang, Ying-Jie. 2024. PRODH safeguards human naive pluripotency by limiting mitochondrial oxidative phosphorylation and reactive oxygen species production. In EMBO reports, 25, 2015-2044. doi:10.1038/s44319-024-00110-z. https://pubmed.ncbi.nlm.nih.gov/38480845/

3. Huynh, Thi Yen Ly, Oscilowska, Ilona, Szoka, Lukasz, Miltyk, Wojciech, Palka, Jerzy. 2022. Metformin Induces PRODH/POX-Dependent Apoptosis in Breast Cancer Cells. In Frontiers in molecular biosciences, 9, 869413. doi:10.3389/fmolb.2022.869413. https://pubmed.ncbi.nlm.nih.gov/35733940/

4. Lewoniewska, Sylwia, Oscilowska, Ilona, Forlino, Antonella, Palka, Jerzy. 2021. Understanding the Role of Estrogen Receptor Status in PRODH/POX-Dependent Apoptosis/Survival in Breast Cancer Cells. In Biology, 10, . doi:10.3390/biology10121314. https://pubmed.ncbi.nlm.nih.gov/34943229/

5. Misiura, Magdalena, Ościłowska, Ilona, Bielawska, Katarzyna, Pałka, Jerzy, Miltyk, Wojciech. 2021. PRODH/POX-Dependent Celecoxib-Induced Apoptosis in MCF-7 Breast Cancer. In Pharmaceuticals (Basel, Switzerland), 14, . doi:10.3390/ph14090874. https://pubmed.ncbi.nlm.nih.gov/34577574/

6. Lv, Qingbo, Li, Duanbin, Zhao, Liding, Shang, Min, Zhang, Wenbin. 2024. Proline metabolic reprogramming modulates cardiac remodeling induced by pressure overload in the heart. In Science advances, 10, eadl3549. doi:10.1126/sciadv.adl3549. https://pubmed.ncbi.nlm.nih.gov/38718121/