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 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. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	John J. Shin [verfasserIn] Qurratulain Aftab [verfasserIn] Pamela Austin [verfasserIn] Jennifer A. McQueen [verfasserIn] Tak Poon [verfasserIn] Shu Chen Li [verfasserIn] Barry P. Young [verfasserIn] Calvin D. Roskelley [verfasserIn] Christopher J. R. Loewen [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2016

Schlagwörter:	AP-3 complex Hap1 cells Mitochondria PAN complex Intracellular acid stress Metabolism

Übergeordnetes Werk:	In: Disease Models & Mechanisms - The Company of Biologists, 2011, 9(2016), 9, Seite 1039-1049
Übergeordnetes Werk:	volume:9 ; year:2016 ; number:9 ; pages:1039-1049

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.1242/dmm.023374

Katalog-ID:	DOAJ026919672

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spelling	10.1242/dmm.023374 doi (DE-627)DOAJ026919672 (DE-599)DOAJe4ad6a9d9de942b1a8efd2584d4da9bd DE-627 ger DE-627 rakwb eng RB1-214 John J. Shin verfasserin aut Systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. AP-3 complex Hap1 cells Mitochondria PAN complex Intracellular acid stress Metabolism Medicine R Pathology Qurratulain Aftab verfasserin aut Pamela Austin verfasserin aut Jennifer A. McQueen verfasserin aut Tak Poon verfasserin aut Shu Chen Li verfasserin aut Barry P. Young verfasserin aut Calvin D. Roskelley verfasserin aut Christopher J. R. Loewen verfasserin aut In Disease Models & Mechanisms The Company of Biologists, 2011 9(2016), 9, Seite 1039-1049 (DE-627)578531917 (DE-600)2451104-3 17548411 nnns volume:9 year:2016 number:9 pages:1039-1049 https://doi.org/10.1242/dmm.023374 kostenfrei https://doaj.org/article/e4ad6a9d9de942b1a8efd2584d4da9bd kostenfrei http://dmm.biologists.org/content/9/9/1039 kostenfrei https://doaj.org/toc/1754-8403 Journal toc kostenfrei https://doaj.org/toc/1754-8411 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2016 9 1039-1049
allfields_unstemmed	10.1242/dmm.023374 doi (DE-627)DOAJ026919672 (DE-599)DOAJe4ad6a9d9de942b1a8efd2584d4da9bd DE-627 ger DE-627 rakwb eng RB1-214 John J. Shin verfasserin aut Systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. AP-3 complex Hap1 cells Mitochondria PAN complex Intracellular acid stress Metabolism Medicine R Pathology Qurratulain Aftab verfasserin aut Pamela Austin verfasserin aut Jennifer A. McQueen verfasserin aut Tak Poon verfasserin aut Shu Chen Li verfasserin aut Barry P. Young verfasserin aut Calvin D. Roskelley verfasserin aut Christopher J. R. Loewen verfasserin aut In Disease Models & Mechanisms The Company of Biologists, 2011 9(2016), 9, Seite 1039-1049 (DE-627)578531917 (DE-600)2451104-3 17548411 nnns volume:9 year:2016 number:9 pages:1039-1049 https://doi.org/10.1242/dmm.023374 kostenfrei https://doaj.org/article/e4ad6a9d9de942b1a8efd2584d4da9bd kostenfrei http://dmm.biologists.org/content/9/9/1039 kostenfrei https://doaj.org/toc/1754-8403 Journal toc kostenfrei https://doaj.org/toc/1754-8411 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2016 9 1039-1049
allfieldsGer	10.1242/dmm.023374 doi (DE-627)DOAJ026919672 (DE-599)DOAJe4ad6a9d9de942b1a8efd2584d4da9bd DE-627 ger DE-627 rakwb eng RB1-214 John J. Shin verfasserin aut Systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. AP-3 complex Hap1 cells Mitochondria PAN complex Intracellular acid stress Metabolism Medicine R Pathology Qurratulain Aftab verfasserin aut Pamela Austin verfasserin aut Jennifer A. McQueen verfasserin aut Tak Poon verfasserin aut Shu Chen Li verfasserin aut Barry P. Young verfasserin aut Calvin D. Roskelley verfasserin aut Christopher J. R. Loewen verfasserin aut In Disease Models & Mechanisms The Company of Biologists, 2011 9(2016), 9, Seite 1039-1049 (DE-627)578531917 (DE-600)2451104-3 17548411 nnns volume:9 year:2016 number:9 pages:1039-1049 https://doi.org/10.1242/dmm.023374 kostenfrei https://doaj.org/article/e4ad6a9d9de942b1a8efd2584d4da9bd kostenfrei http://dmm.biologists.org/content/9/9/1039 kostenfrei https://doaj.org/toc/1754-8403 Journal toc kostenfrei https://doaj.org/toc/1754-8411 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2016 9 1039-1049
allfieldsSound	10.1242/dmm.023374 doi (DE-627)DOAJ026919672 (DE-599)DOAJe4ad6a9d9de942b1a8efd2584d4da9bd DE-627 ger DE-627 rakwb eng RB1-214 John J. Shin verfasserin aut Systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. AP-3 complex Hap1 cells Mitochondria PAN complex Intracellular acid stress Metabolism Medicine R Pathology Qurratulain Aftab verfasserin aut Pamela Austin verfasserin aut Jennifer A. McQueen verfasserin aut Tak Poon verfasserin aut Shu Chen Li verfasserin aut Barry P. Young verfasserin aut Calvin D. Roskelley verfasserin aut Christopher J. R. Loewen verfasserin aut In Disease Models & Mechanisms The Company of Biologists, 2011 9(2016), 9, Seite 1039-1049 (DE-627)578531917 (DE-600)2451104-3 17548411 nnns volume:9 year:2016 number:9 pages:1039-1049 https://doi.org/10.1242/dmm.023374 kostenfrei https://doaj.org/article/e4ad6a9d9de942b1a8efd2584d4da9bd kostenfrei http://dmm.biologists.org/content/9/9/1039 kostenfrei https://doaj.org/toc/1754-8403 Journal toc kostenfrei https://doaj.org/toc/1754-8411 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2016 9 1039-1049
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source	In Disease Models & Mechanisms 9(2016), 9, Seite 1039-1049 volume:9 year:2016 number:9 pages:1039-1049
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callnumber-first	R - Medicine
author	John J. Shin
spellingShingle	John J. Shin misc RB1-214 misc AP-3 complex misc Hap1 cells misc Mitochondria misc PAN complex misc Intracellular acid stress misc Metabolism misc Medicine misc R misc Pathology Systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets
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topic_title	RB1-214 Systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets AP-3 complex Hap1 cells Mitochondria PAN complex Intracellular acid stress Metabolism
topic	misc RB1-214 misc AP-3 complex misc Hap1 cells misc Mitochondria misc PAN complex misc Intracellular acid stress misc Metabolism misc Medicine misc R misc Pathology
topic_unstemmed	misc RB1-214 misc AP-3 complex misc Hap1 cells misc Mitochondria misc PAN complex misc Intracellular acid stress misc Metabolism misc Medicine misc R misc Pathology
topic_browse	misc RB1-214 misc AP-3 complex misc Hap1 cells misc Mitochondria misc PAN complex misc Intracellular acid stress misc Metabolism misc Medicine misc R misc Pathology
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title	Systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets
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title_full	Systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets
author_sort	John J. Shin
journal	Disease Models & Mechanisms
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author_browse	John J. Shin Qurratulain Aftab Pamela Austin Jennifer A. McQueen Tak Poon Shu Chen Li Barry P. Young Calvin D. Roskelley Christopher J. R. Loewen
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author-letter	John J. Shin
doi_str_mv	10.1242/dmm.023374
author2-role	verfasserin
title_sort	systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets
callnumber	RB1-214
title_auth	Systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets
abstract	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.
abstractGer	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.
abstract_unstemmed	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.
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container_issue	9
title_short	Systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets
url	https://doi.org/10.1242/dmm.023374 https://doaj.org/article/e4ad6a9d9de942b1a8efd2584d4da9bd http://dmm.biologists.org/content/9/9/1039 https://doaj.org/toc/1754-8403 https://doaj.org/toc/1754-8411
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author2	Qurratulain Aftab Pamela Austin Jennifer A. McQueen Tak Poon Shu Chen Li Barry P. Young Calvin D. Roskelley Christopher J. R. Loewen
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up_date	2024-07-03T23:36:33.874Z
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