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Research Highlight | Jan 3, 2017

Hypoxia team members make game-changing findings about how tumour cells control oxygen consumption

Wouter,B_2011


Members of TFRI’s hypoxia research team have made some game-changing findings when it comes to understanding how tumour cells regulate their oxygen levels to maximize survival.

Published in Nature Cell Biology http://www.nature.com/ncb/journal/v18/n7/full/ncb3376.html (July 2016), the study’s authors reported a novel discovery of how tumour cells control the amount of oxygen they consume under conditions of limited oxygen availability.

Cancer patients respond poorly to treatment if their tumours are low in oxygen, a state known as hypoxia. These tumours are more likely to grow and spread aggressively.

It was previously known that the transcription factor hypoxia-inducible factor (HIF) controlled oxygen consumption by mitochondria. This paper demonstrated how oxygen consumption by other processes is inhibited when oxygen is scarce. This information is critical, because cells die if they are unable to shut down this consumption.

Molecular mechanisms responsible for this regulation were also suggested in the present study. Protein-tyrosine phosphatase-1B (PTP1B) is needed for Her2/Neu-driven breast cancer (BC) in mice, although the underlying mechanism and human relevance is not certain. It was found that PTP1B acts via a protein called RNF213 to suppress α-KGDD activity and non-mitochondrial oxygen consumption – a pathway that is needed for breast cancer to survive in the hypoxic tumour microenvironment.

This paper (first author Robert S. Banh) opens up an entirely new area of investigation on how cells control oxygen consumption in tumours. Consumption is regulated by the action of a phosphatase that could potentially be targeted with new drugs.

In addition, the mechanism involves the inactivation of RNF213. The gene encoding this protein is mutated in patients with a rare disease known as Moyamoya. Consequently, the discovery also sheds light on the understanding of this vascular disease, in addition to its groundbreaking relevance to many cancers.

Study: PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia

Authors: Robert S. Banh, Caterina Iorio, Richard Marcotte, Yang Xu, Dan Cojocari, Anas Abdel Rahman, Judy Pawling, Wei Zhang, Ankit Sinha, Christopher M. Rose, Marta Isasa, Shuang Zhang, Ronald Wu, Carl Virtanen, Toshiaki Hitomi, Toshiyuki Habu, Sachdev S. Sidhu, Akio Koizumi, Sarah E.Wilkins, Thomas Kislinger, Steven P. Gygi, Christopher J. Schofield, James W. Dennis, Bradly G. Wouters, and Benjamin G. Neel

Funding: This work was funded by NIH grant R37 CA49152 and Canadian Institutes of Health Research (CIHR) grant 120593 (to B.G.N.), CIHR grant 62975 (to J.W.D.), CIHR grant 136956 (to S.S.S.), CIHR grant 133615 (to T.K.), Terry Fox New Frontiers Research Program PPG09-02005 (to B.G.W.), Cancer Research-UK and the Wellcome Trust (to S.E.W. and C.J.S), NIH grant GM96745 (to S.P.G.) and Kiban Kenkyu grant A-25253047 to A.K. Work in the Neel and Wouters laboratories was partially supported by the Princess Margaret Cancer Foundation and the Ontario Ministry of Health and Long Term Care.