Polyamine pathway activity promotes cysteine essentiality in cancer cells

Zhang, T., Bauer, C., Newman, A. C., Uribe, A. H., Athineos, D., Blyth, K. and Maddocks, O. D.K. (2020) Polyamine pathway activity promotes cysteine essentiality in cancer cells. Nature Metabolism, 2, pp. 1062-1076. (doi: 10.1038/s42255-020-0253-2) (PMID:32747794)

Abstract

Cancer cells have high demands for non-essential amino acids (NEAAs), which are precursors for anabolic and antioxidant pathways that support cell survival and proliferation. It is well-established that cancer cells consume the NEAA cysteine, and that cysteine deprivation can induce cell death; however, the specific factors governing acute sensitivity to cysteine starvation are poorly characterized. Here, we show that that neither expression of enzymes for cysteine synthesis nor availability of the primary precursor methionine correlated with acute sensitivity to cysteine starvation. We observed a strong correlation between efflux of the methionine-derived metabolite methylthioadenosine (MTA) and sensitivity to cysteine starvation. MTA efflux results from genetic deletion of methylthioadenosine phosphorylase (MTAP), which is frequently deleted in cancers. We show that MTAP loss upregulates polyamine metabolism which, concurrently with cysteine withdrawal, promotes elevated reactive oxygen species and prevents cell survival. Our results reveal an unexplored metabolic weakness at the intersection of polyamine and cysteine metabolism.

• Item Type: Articles
• Additional Information: We wish to thank the staff of the Biological Services facility at the Cancer Research UK (CRUK) Beatson Institute, funded by CRUK (A18076 & A17196). K.B. and D.A. are core funded by CRUK (A17196 & A29799). O.D.K.M., T.Z., C.B. and A.C.N. were funded by a Cancer Research UK Career Development Fellowship awarded to O.D.K.M. (C53309/A19702).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Blyth, Professor Karen and Maddocks, Professor Oliver and Newman, Dr Alice and Zhang, Mr Tong and Athineos, Mr Dimitris and Bauer, Dr Christin
• Authors: Zhang, T., Bauer, C., Newman, A. C., Uribe, A. H., Athineos, D., Blyth, K., and Maddocks, O. D.K.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Metabolism
• Publisher: Nature Research
• ISSN: 2522-5812
• ISSN (Online): 2522-5812
• Published Online: 03 August 2020
• Copyright Holders: Copyright © 2020 Springer Nature
• First Published: First published in Nature Metabolism 2:1062–1076
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
171982		Targeting Tumour Metabolism for Cancer Therapy and Diagnosis.	Oliver Maddocks	Cancer Research UK (CRUK)	C53309/A19702	Institute of Cancer Sciences