Systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets

A hallmark of all primary and metastatic tumours is their high rate of glucose uptake and glycolysis. A consequence of the glycolytic phenotype is the accumulation of metabolic acid; hence, tumour cells experience considerable intracellular acid stress. To compensate, tumour cells upregulate acid pu...

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Main Authors: John J. Shin (Author), Qurratulain Aftab (Author), Pamela Austin (Author), Jennifer A. McQueen (Author), Tak Poon (Author), Shu Chen Li (Author), Barry P. Young (Author), Calvin D. Roskelley (Author), Christopher J. R. Loewen (Author)
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Published: The Company of Biologists, 2016-09-01T00:00:00Z.
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100 1 0 |a John J. Shin  |e author 
700 1 0 |a Qurratulain Aftab  |e author 
700 1 0 |a Pamela Austin  |e author 
700 1 0 |a Jennifer A. McQueen  |e author 
700 1 0 |a Tak Poon  |e author 
700 1 0 |a Shu Chen Li  |e author 
700 1 0 |a Barry P. Young  |e author 
700 1 0 |a Calvin D. Roskelley  |e author 
700 1 0 |a Christopher J. R. Loewen  |e author 
245 0 0 |a Systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets 
260 |b The Company of Biologists,   |c 2016-09-01T00:00:00Z. 
500 |a 1754-8403 
500 |a 1754-8411 
500 |a 10.1242/dmm.023374 
520 |a A hallmark of all primary and metastatic tumours is their high rate of glucose uptake and glycolysis. A consequence of the glycolytic phenotype is the accumulation of metabolic acid; hence, tumour cells experience considerable intracellular acid stress. To compensate, tumour cells upregulate acid pumps, which expel the metabolic acid into the surrounding tumour environment, resulting in alkalization of intracellular pH and acidification of the tumour microenvironment. Nevertheless, we have only a limited understanding of the consequences of altered intracellular pH on cell physiology, or of the genes and pathways that respond to metabolic acid stress. We have used yeast as a genetic model for metabolic acid stress with the rationale that the metabolic changes that occur in cancer that lead to intracellular acid stress are likely fundamental. Using a quantitative systems biology approach we identified 129 genes required for optimal growth under conditions of metabolic acid stress. We identified six highly conserved protein complexes with functions related to oxidative phosphorylation (mitochondrial respiratory chain complex III and IV), mitochondrial tRNA biosynthesis [glutamyl-tRNA(Gln) amidotransferase complex], histone methylation (Set1C-COMPASS), lysosome biogenesis (AP-3 adapter complex), and mRNA processing and P-body formation (PAN complex). We tested roles for two of these, AP-3 adapter complex and PAN deadenylase complex, in resistance to acid stress using a myeloid leukaemia-derived human cell line that we determined to be acid stress resistant. Loss of either complex inhibited growth of Hap1 cells at neutral pH and caused sensitivity to acid stress, indicating that AP-3 and PAN complexes are promising new targets in the treatment of cancer. Additionally, our data suggests that tumours may be genetically sensitized to acid stress and hence susceptible to acid stress-directed therapies, as many tumours accumulate mutations in mitochondrial respiratory chain complexes required for their proliferation. 
546 |a EN 
690 |a AP-3 complex 
690 |a Hap1 cells 
690 |a Mitochondria 
690 |a PAN complex 
690 |a Intracellular acid stress 
690 |a Metabolism 
690 |a Medicine 
690 |a R 
690 |a Pathology 
690 |a RB1-214 
655 7 |a article  |2 local 
786 0 |n Disease Models & Mechanisms, Vol 9, Iss 9, Pp 1039-1049 (2016) 
787 0 |n http://dmm.biologists.org/content/9/9/1039 
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787 0 |n https://doaj.org/toc/1754-8411 
856 4 1 |u https://doaj.org/article/e4ad6a9d9de942b1a8efd2584d4da9bd  |z Connect to this object online.