University of Leicester
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Increased mitochondrial proline metabolism sustains proliferation and survival of colorectal cancer cells

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posted on 2022-03-11, 09:31 authored by Saif Sattar Alaqbi, Lynsey Burke, Inna Guterman, Caleb Green, Kevin West, Raquel Palacios-Gallego, Hong Cai, Constantinos Alexandrou, Ni Ni Moe Myint, Emma Parrott, Lynne M Howells, Jennifer A Higgins, Donald JL Jones, Rajinder Singh, Robert G Britton, Cristina Tufarelli, Anne Thomas, Alessandro Rufini
Research into the metabolism of the non-essential amino acid (NEAA) proline in cancer has gained traction in recent years. The last step in the proline biosynthesis pathway is catalyzed by pyrroline-5-carboxylate reductase (PYCR) enzymes. There are three PYCR enzymes: mitochondrial PYCR1 and 2 and cytosolic PYCR3 encoded by separate genes. The expression of the PYCR1 gene is increased in numerous malignancies and correlates with poor prognosis. PYCR1 expression sustains cancer cells’ proliferation and survival and several mechanisms have been implicated to explain its oncogenic role. It has been suggested that the biosynthesis of proline is key to sustain protein synthesis, support mitochondrial function and nucleotide biosynthesis. However, the links between proline metabolism and cancer remain ill-defined and are likely to be tissue specific. Here we use a combination of human dataset, human tissue and mouse models to show that the expression levels of the proline biosynthesis enzymes are significantly increased during colorectal tumorigenesis. Functionally, the expression of mitochondrial PYCRs is necessary for cancer cells’ survival and proliferation. However, the phenotypic consequences of PYCRs depletion could not be rescued by external supplementation with either proline or nucleotides. Overall, our data suggest that, despite the mechanisms underlying the role of proline metabolism in colorectal tumorigenesis remain elusive, targeting the proline biosynthesis pathway is a suitable approach for the development of novel anti-cancer therapies.


This work was supported by the Cancer Prevention Research Trust (CPRT), with assistance from Cancer Research UK in conjunction with the Department of Health as part of an ECMC grant [C325/A15575]. L.B. and C. A. were funded by PhD fellowships from the CPRT (grant code TM60004-CPRT and RM60G0499), S.S.A. was funded by a studentship from the Iraqi Government (grant code M60RT115), and I.G. was funded by a grant from the CPRT (grant code RM60G0665-CPRT). C.G. and N.N.M.M were supported by a Medical Research Council Doctoral Training Grant. C.T. is supported by a Wellcome Trust Research Career Re-entry Fellowship (210911/Z/18/Z, ’Exploiting transcription of repetitive DNA to study early events in colorectal cancer’). R.P.G. is supported through a Development Grant to A.R. and C.T. from the charity Hope Against Cancer (, grant code RM60G0751). D.J.L.J. is supported by the National Institute for Health Research Leicester Biomedical Research Centre.



Alaqbi SS, Burke L, Guterman I, Green C, West K, Palacios-Gallego R, et al. (2022) Increased mitochondrial proline metabolism sustains proliferation and survival of colorectal cancer cells. PLoS ONE 17(2): e0262364.

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Leicester Cancer Research Centre


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