Cells within solid tumours can become deprived of nutrients; in order to survive, they need to invoke mechanisms to conserve these resources. Using cancer cells in culture in the absence of key nutrients, we have explored the roles of two potential survival mechanisms, autophagy and elongation factor 2 kinase (eEF2K), which, when activated, inhibits the resource-intensive elongation stage of protein synthesis. Both processes are regulated through the nutrient-sensitive AMP-activated protein kinase and mechanistic target of rapamycin complex 1 signalling pathways. We find that disabling both autophagy and eEF2K strongly compromises the survival of nutrient-deprived lung and breast cancer cells, whereas, for example, knocking out eEF2K alone has little effect. Contrary to some earlier reports, we find no evidence that eEF2K regulates autophagy. Unexpectedly, eEF2K does not facilitate survival of prostate cancer PC3 cells. Thus, eEF2K and autophagy enable survival of certain cell-types in a mutually complementary manner. To explore this further, we generated, by selection, cells which were able to survive nutrient starvation even when autophagy and eEF2K were disabled. Proteome profiling using mass spectrometry revealed that these ‘resistant’ cells showed lower levels of diverse proteins which are required for energy-consuming processes such as protein and fatty acid synthesis, although different clones of ‘resistant cells’ appear to adapt in dissimilar ways. Our data provide further information of the ways that human cells cope with nutrient limitation and to understanding of the utility of eEF2K as a potential target in oncology.
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April 2021
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Serine pyrophosphorylation by the inositol pyrophosphate 5-IP7 keeps cellular MYC levels in check. Elevation in MYC downstream to 5-IP7 depletion influences cell fate in response to environmental cues. For further information see the article in this issue by Lolla and colleagues (pp. 1647–1661). Image was created by Akruti Shah using BioRender.
Research Article|
April 21 2021
Elongation factor eEF2 kinase and autophagy jointly promote survival of cancer cells
Roman V. Lenchine;
Roman V. Lenchine
Data curation, Formal analysis, Investigation, Methodology, Writing - original draft
1Lifelong Health, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
2The University of Adelaide, Adelaide, SA 5000, Australia
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Sushma R. Rao;
Sushma R. Rao
2The University of Adelaide, Adelaide, SA 5000, Australia
3Proteomics, Metabolomics and MS-Imaging Facility, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
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Xuemin Wang;
Xuemin Wang
Conceptualization, Formal analysis, Supervision, Investigation, Methodology, Project administration
1Lifelong Health, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
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Danielle Meiwen Fang;
Danielle Meiwen Fang
1Lifelong Health, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
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Christopher G. Proud
Conceptualization, Data curation, Supervision, Funding acquisition, Validation, Project administration, Writing - review & editing
1Lifelong Health, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
Correspondence: Christopher G Proud (christopher.proud@sahmri.com)
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Publisher: Portland Press Ltd
Received:
March 01 2021
Revision Received:
March 22 2021
Accepted:
March 29 2021
Accepted Manuscript online:
March 29 2021
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2021
Biochem J (2021) 478 (8): 1547–1569.
Article history
Received:
March 01 2021
Revision Received:
March 22 2021
Accepted:
March 29 2021
Accepted Manuscript online:
March 29 2021
Citation
Roman V. Lenchine, Sushma R. Rao, Xuemin Wang, Danielle Meiwen Fang, Christopher G. Proud; Elongation factor eEF2 kinase and autophagy jointly promote survival of cancer cells. Biochem J 30 April 2021; 478 (8): 1547–1569. doi: https://doi.org/10.1042/BCJ20210126
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