Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions

Westbrook, R. L. et al. (2022) Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions. Cell Reports, 38(5), 110320. (doi: 10.1016/j.celrep.2022.110320) (PMID:35108535) (PMCID:PMC8822494)

Abstract

The demands of cancer cell proliferation alongside an inadequate angiogenic response lead to insufficient oxygen availability in the tumor microenvironment. Within the mitochondria, oxygen is the major electron acceptor for NADH, with the result that the reducing potential produced through tricarboxylic acid (TCA) cycle activity and mitochondrial respiration are functionally linked. As the oxidizing activity of the TCA cycle is required for efficient synthesis of anabolic precursors, tumoral hypoxia could lead to a cessation of proliferation without another means of correcting the redox imbalance. We show that in hypoxic conditions, mitochondrial pyrroline 5-carboxylate reductase 1 (PYCR1) activity is increased, oxidizing NADH with the synthesis of proline as a by-product. We further show that PYCR1 activity is required for the successful maintenance of hypoxic regions by permitting continued TCA cycle activity, and that its loss leads to significantly increased hypoxia in vivo and in 3D culture, resulting in widespread cell death.

• Item Type: Articles
• Additional Information: The authors would like to acknowledge funding from Cancer Research UK to R.L.W., C.E.G., K.L.E., E.V.-S., L.A.V., and P.D.W. (C42109/A26982 and C42109/A24747).
• Keywords: Redox, cancer, proline, mitochondria, hypoxia, NADH, PYCR1.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Nixon, Mr Colin
• Authors: Westbrook, R. L., Bridges, E., Roberts, J., Escribano-Gonzalez, C., Eales, K. L., Vettore, L. A., Walker, P. D., Vera-Siguenza, E., Rana, H., Cuozzo, F., Eskla, K.-L., Vellama, H., Shaaban, A., Nixon, C., Luuk, H., Lavery, G. G., Hodson, D. J., Harris, A. L., and Tennant, D. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Reports
• Publisher: Elsevier (Cell Press)
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Cell Reports 38(5): 110320
• Publisher Policy: Reproduced under a Creative Commons License