Pyrroline-5-carboxylate reductase 1 reprograms proline metabolism to drive breast cancer stemness under psychological stress

• Published in: Cell death & disease Vol. 14; no. 10; p. 682
• Main Authors: Cui, Bai, He, Bin, Huang, Yanping, Wang, Cenxin, Luo, Huandong, Lu, Jinxin, Su, Keyu, Zhang, Xiaoyu, Luo, Yuanyuan, Zhao, Zhuoran, Yang, Yuqing, Zhang, Yunkun, An, Fan, Wang, Hong, Lam, Eric W.-F., Kelley, Keith W., Wang, Ling, Liu, Quentin, Peng, Fei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.10.2023; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/100; 13/31; 13/51; 13/89; 38/90; 38/91; 631/532/71; 631/67/1347; 64/60; 82/1; 82/80; Ablation; Amino acids; Antibodies; Biochemistry; Biomedical and Life Sciences; Biosynthesis; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Carboxylate reductase; Cell Biology; Cell Culture; Cyclic GMP; delta-1-Pyrroline-5-Carboxylate Reductase; Drug resistance; Female; Genomics; Hospitals; Humans; Immunology; Life Sciences; Medical prognosis; Metabolism; Metastases; Neoplasm Recurrence, Local; Oncology; Oxidoreductases; Phenotypes; Proline; Proline - metabolism; Proteins; Pyrroline-5-carboxylate reductase; Signal transduction; Spheroids; Stem cells; Stress; Tumorigenesis; Tumors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-06200-5

Cancer stem-like cells (CSCs) contribute to cancer metastasis, drug resistance and tumor relapse, yet how amino acid metabolism promotes CSC maintenance remains exclusive. Here, we identify that proline synthetase PYCR1 is critical for breast cancer stemness and tumor growth. Mechanistically, PYCR1-synthesized proline activates cGMP-PKG signaling to enhance cancer stem-like traits. Importantly, cGMP-PKG signaling mediates psychological stress-induced cancer stem-like phenotypes and tumorigenesis. Ablation of PYCR1 markedly reverses psychological stress-induced proline synthesis, cGMP-PKG signaling activation and cancer progression. Clinically, PYCR1 and cGMP-PKG signaling components are highly expressed in breast tumor specimens, conferring poor survival in breast cancer patients. Targeting proline metabolism or cGMP-PKG signaling pathway provides a potential therapeutic strategy for breast patients undergoing psychological stress. Collectively, our findings unveil that PYCR1-enhanced proline synthesis displays a critical role in maintaining breast cancer stemness.