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

Rebecca Westbrook, Esther Bridges, Jennie Roberts, Cristina Escribano Gonzalez, Katherine Eales, Lisa Vettore, Paul Walker, Elias Vera-Siguenza, Himani Rana, Federica Cuozzo, Kattri-Liis Eskla, Hans Vellama, Abeer Shaaban, Colin Nixon, Hendrik Luuk, Gareth Lavery, David Hodson, Adrian L Harris, Daniel Tennant

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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.

Original languageEnglish
Article number110320
Number of pages15
JournalCell Reports
Volume38
Issue number5
DOIs
Publication statusPublished - 1 Feb 2022

Bibliographical note

Funding 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). We would also like to acknowledge Professor Reuven Agami, who kindly gifted the PYCR1?/? line and control. The graphical abstract was created with BioRender.com. Finally, we would like to acknowledge the support and resources of the Birmingham Metabolic Tracer Analysis Core. R.L.W. E.B. A.S. H.L. A.L.H. and D.A.T. conceptualized the study and designed the methodology. R.L.W. E.B. C.E.G. J.R. H.R. K.L.E. K.-L.E. H.V. E.V.-S. L.A.V. P.D.W. F.C. and C.N. performed investigations. E.V.-S. E.B. R.L.W. K.-L.E. H.V. C.N. and D.A.T. performed formal analysis and data visualization. G.G.L. D.J.H. A.S. H.L. C.N. A.L.H. and D.A.T. provided resources. R.L.W. E.B. J.B. C.N. and D.A.T. wrote the original manuscript draft, while all authors contributed to reviewing and editing of the manuscript. The authors declare no competing interests.

Funding 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 ). We would also like to acknowledge Professor Reuven Agami, who kindly gifted the PYCR1 −/− line and control. The graphical abstract was created with BioRender.com. Finally, we would like to acknowledge the support and resources of the Birmingham Metabolic Tracer Analysis Core.

Publisher Copyright:
© 2022 The Authors

Keywords

  • hypoxia
  • proline
  • PYCR1
  • redox
  • cancer
  • mitochondria
  • NADH

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