Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells
Metabolic reprogramming is now considered a hallmark of cancer cells. KRas-driven cancer cells use glutaminolysis to generate the tricarboxylic acid cycle intermediate α-ketoglutarate via a transamination reaction between glutamate and oxaloacetate. We reported previously that exogenously supplied u...
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| description | Metabolic reprogramming is now considered a hallmark of cancer cells. KRas-driven cancer cells use glutaminolysis to generate the tricarboxylic acid cycle intermediate α-ketoglutarate via a transamination reaction between glutamate and oxaloacetate. We reported previously that exogenously supplied unsaturated fatty acids could be used to synthesize phosphatidic acid–a lipid second messenger that activates both mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTOR complex 2 (mTORC2). A key target of mTORC2 is Akt–a kinase that promotes survival and regulates cell metabolism. We report here that mono-unsaturated oleic acid stimulates the phosphorylation of ATP citrate lyase (ACLY) at the Akt phosphorylation site at S455 in an mTORC2 dependent manner. Inhibition of ACLY in KRas-driven cancer cells in the absence of serum resulted in loss of cell viability. We examined the impact of glutamine (Gln) deprivation in combination with inhibition of ACLY on the viability of KRas-driven cancer cells. While Gln deprivation was somewhat toxic to KRas-driven cancer cells by itself, addition of the ACLY inhibitor SB-204990 increased the loss of cell viability. However, the transaminase inhibitor aminooxyacetate was minimally toxic and the combination of SB-204990 and aminooxtacetate led to significant loss of cell viability and strong cleavage of poly-ADP ribose polymerase–indicating apoptotic cell death. This effect was not observed in MCF7 breast cancer cells that do not have a KRas mutation or in BJ-hTERT human fibroblasts which have no oncogenic mutation. These data reveal a synthetic lethality between inhibition of glutamate oxaloacetate transaminase and ACLY inhibition that is specific for KRas-driven cancer cells and the apparent metabolic reprogramming induced by activating mutations to KRas. |
| doi_str_mv | 10.1371/journal.pone.0276579 |
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KRas-driven cancer cells use glutaminolysis to generate the tricarboxylic acid cycle intermediate α-ketoglutarate via a transamination reaction between glutamate and oxaloacetate. We reported previously that exogenously supplied unsaturated fatty acids could be used to synthesize phosphatidic acid–a lipid second messenger that activates both mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTOR complex 2 (mTORC2). A key target of mTORC2 is Akt–a kinase that promotes survival and regulates cell metabolism. We report here that mono-unsaturated oleic acid stimulates the phosphorylation of ATP citrate lyase (ACLY) at the Akt phosphorylation site at S455 in an mTORC2 dependent manner. Inhibition of ACLY in KRas-driven cancer cells in the absence of serum resulted in loss of cell viability. We examined the impact of glutamine (Gln) deprivation in combination with inhibition of ACLY on the viability of KRas-driven cancer cells. While Gln deprivation was somewhat toxic to KRas-driven cancer cells by itself, addition of the ACLY inhibitor SB-204990 increased the loss of cell viability. However, the transaminase inhibitor aminooxyacetate was minimally toxic and the combination of SB-204990 and aminooxtacetate led to significant loss of cell viability and strong cleavage of poly-ADP ribose polymerase–indicating apoptotic cell death. This effect was not observed in MCF7 breast cancer cells that do not have a KRas mutation or in BJ-hTERT human fibroblasts which have no oncogenic mutation. These data reveal a synthetic lethality between inhibition of glutamate oxaloacetate transaminase and ACLY inhibition that is specific for KRas-driven cancer cells and the apparent metabolic reprogramming induced by activating mutations to KRas.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0276579</identifier><identifier>PMID: 36269753</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Adenosine diphosphate ; AKT protein ; Antibodies ; Apoptosis ; ATP ; ATP citrate lyase ; Biology and Life Sciences ; Breast cancer ; Cancer ; Cancer cells ; Cell cycle ; Cell death ; Cell metabolism ; Cell survival ; Cell viability ; Deprivation ; Endoplasmic reticulum ; Enzymes ; Fatty acids ; Fibroblasts ; Gene mutations ; Genetic aspects ; Glutamine ; Insulin ; K-Ras protein ; Ketoglutaric acid ; Kinases ; Lethality ; Lipids ; Lyases ; Medicine and Health Sciences ; Membranes ; Metabolism ; Mitochondria ; Mutation ; Oleic acid ; Oncology, Experimental ; Phosphatidic acid ; Phosphorylation ; Physical Sciences ; Physiological aspects ; Proteins ; Rapamycin ; Research and Analysis Methods ; Ribose ; Synthesis ; Telomerase reverse transcriptase ; TOR protein ; Transaminase ; Transaminases ; Tricarboxylic acid cycle</subject><ispartof>PloS one, 2022-10, Vol.17 (10), p.e0276579-e0276579</ispartof><rights>COPYRIGHT 2022 Public Library of Science</rights><rights>2022 Hatipoglu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 Hatipoglu et al 2022 Hatipoglu et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c669t-b74016652a709379f3623bc3f5687161163249154c4bac6ec116a32eae08a5b43</citedby><cites>FETCH-LOGICAL-c669t-b74016652a709379f3623bc3f5687161163249154c4bac6ec116a32eae08a5b43</cites><orcidid>0000-0003-0900-6946</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9586366/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9586366/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,2098,2917,23849,27907,27908,53774,53776,79351,79352</link.rule.ids></links><search><contributor>Sun, Shi-Yong</contributor><creatorcontrib>Hatipoglu, Ahmet</creatorcontrib><creatorcontrib>Menon, Deepak</creatorcontrib><creatorcontrib>Levy, Talia</creatorcontrib><creatorcontrib>Frias, Maria A</creatorcontrib><creatorcontrib>Foster, David A</creatorcontrib><title>Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells</title><title>PloS one</title><description>Metabolic reprogramming is now considered a hallmark of cancer cells. KRas-driven cancer cells use glutaminolysis to generate the tricarboxylic acid cycle intermediate α-ketoglutarate via a transamination reaction between glutamate and oxaloacetate. We reported previously that exogenously supplied unsaturated fatty acids could be used to synthesize phosphatidic acid–a lipid second messenger that activates both mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTOR complex 2 (mTORC2). A key target of mTORC2 is Akt–a kinase that promotes survival and regulates cell metabolism. We report here that mono-unsaturated oleic acid stimulates the phosphorylation of ATP citrate lyase (ACLY) at the Akt phosphorylation site at S455 in an mTORC2 dependent manner. Inhibition of ACLY in KRas-driven cancer cells in the absence of serum resulted in loss of cell viability. We examined the impact of glutamine (Gln) deprivation in combination with inhibition of ACLY on the viability of KRas-driven cancer cells. While Gln deprivation was somewhat toxic to KRas-driven cancer cells by itself, addition of the ACLY inhibitor SB-204990 increased the loss of cell viability. However, the transaminase inhibitor aminooxyacetate was minimally toxic and the combination of SB-204990 and aminooxtacetate led to significant loss of cell viability and strong cleavage of poly-ADP ribose polymerase–indicating apoptotic cell death. This effect was not observed in MCF7 breast cancer cells that do not have a KRas mutation or in BJ-hTERT human fibroblasts which have no oncogenic mutation. These data reveal a synthetic lethality between inhibition of glutamate oxaloacetate transaminase and ACLY inhibition that is specific for KRas-driven cancer cells and the apparent metabolic reprogramming induced by activating mutations to KRas.</description><subject>Adenosine diphosphate</subject><subject>AKT protein</subject><subject>Antibodies</subject><subject>Apoptosis</subject><subject>ATP</subject><subject>ATP citrate lyase</subject><subject>Biology and Life Sciences</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer cells</subject><subject>Cell cycle</subject><subject>Cell death</subject><subject>Cell metabolism</subject><subject>Cell survival</subject><subject>Cell viability</subject><subject>Deprivation</subject><subject>Endoplasmic reticulum</subject><subject>Enzymes</subject><subject>Fatty acids</subject><subject>Fibroblasts</subject><subject>Gene mutations</subject><subject>Genetic aspects</subject><subject>Glutamine</subject><subject>Insulin</subject><subject>K-Ras protein</subject><subject>Ketoglutaric acid</subject><subject>Kinases</subject><subject>Lethality</subject><subject>Lipids</subject><subject>Lyases</subject><subject>Medicine and Health Sciences</subject><subject>Membranes</subject><subject>Metabolism</subject><subject>Mitochondria</subject><subject>Mutation</subject><subject>Oleic acid</subject><subject>Oncology, Experimental</subject><subject>Phosphatidic acid</subject><subject>Phosphorylation</subject><subject>Physical Sciences</subject><subject>Physiological aspects</subject><subject>Proteins</subject><subject>Rapamycin</subject><subject>Research and Analysis Methods</subject><subject>Ribose</subject><subject>Synthesis</subject><subject>Telomerase reverse transcriptase</subject><subject>TOR protein</subject><subject>Transaminase</subject><subject>Transaminases</subject><subject>Tricarboxylic acid 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glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells</title><author>Hatipoglu, Ahmet ; Menon, Deepak ; Levy, Talia ; Frias, Maria A ; Foster, David A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c669t-b74016652a709379f3623bc3f5687161163249154c4bac6ec116a32eae08a5b43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Adenosine diphosphate</topic><topic>AKT protein</topic><topic>Antibodies</topic><topic>Apoptosis</topic><topic>ATP</topic><topic>ATP citrate lyase</topic><topic>Biology and Life Sciences</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cancer cells</topic><topic>Cell cycle</topic><topic>Cell death</topic><topic>Cell metabolism</topic><topic>Cell survival</topic><topic>Cell viability</topic><topic>Deprivation</topic><topic>Endoplasmic reticulum</topic><topic>Enzymes</topic><topic>Fatty acids</topic><topic>Fibroblasts</topic><topic>Gene mutations</topic><topic>Genetic aspects</topic><topic>Glutamine</topic><topic>Insulin</topic><topic>K-Ras protein</topic><topic>Ketoglutaric acid</topic><topic>Kinases</topic><topic>Lethality</topic><topic>Lipids</topic><topic>Lyases</topic><topic>Medicine and Health Sciences</topic><topic>Membranes</topic><topic>Metabolism</topic><topic>Mitochondria</topic><topic>Mutation</topic><topic>Oleic acid</topic><topic>Oncology, Experimental</topic><topic>Phosphatidic acid</topic><topic>Phosphorylation</topic><topic>Physical Sciences</topic><topic>Physiological aspects</topic><topic>Proteins</topic><topic>Rapamycin</topic><topic>Research and Analysis Methods</topic><topic>Ribose</topic><topic>Synthesis</topic><topic>Telomerase reverse transcriptase</topic><topic>TOR protein</topic><topic>Transaminase</topic><topic>Transaminases</topic><topic>Tricarboxylic acid 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Talia</au><au>Frias, Maria A</au><au>Foster, David A</au><au>Sun, Shi-Yong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells</atitle><jtitle>PloS one</jtitle><date>2022-10-21</date><risdate>2022</risdate><volume>17</volume><issue>10</issue><spage>e0276579</spage><epage>e0276579</epage><pages>e0276579-e0276579</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Metabolic reprogramming is now considered a hallmark of cancer cells. KRas-driven cancer cells use glutaminolysis to generate the tricarboxylic acid cycle intermediate α-ketoglutarate via a transamination reaction between glutamate and oxaloacetate. We reported previously that exogenously supplied unsaturated fatty acids could be used to synthesize phosphatidic acid–a lipid second messenger that activates both mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTOR complex 2 (mTORC2). A key target of mTORC2 is Akt–a kinase that promotes survival and regulates cell metabolism. We report here that mono-unsaturated oleic acid stimulates the phosphorylation of ATP citrate lyase (ACLY) at the Akt phosphorylation site at S455 in an mTORC2 dependent manner. Inhibition of ACLY in KRas-driven cancer cells in the absence of serum resulted in loss of cell viability. We examined the impact of glutamine (Gln) deprivation in combination with inhibition of ACLY on the viability of KRas-driven cancer cells. While Gln deprivation was somewhat toxic to KRas-driven cancer cells by itself, addition of the ACLY inhibitor SB-204990 increased the loss of cell viability. However, the transaminase inhibitor aminooxyacetate was minimally toxic and the combination of SB-204990 and aminooxtacetate led to significant loss of cell viability and strong cleavage of poly-ADP ribose polymerase–indicating apoptotic cell death. This effect was not observed in MCF7 breast cancer cells that do not have a KRas mutation or in BJ-hTERT human fibroblasts which have no oncogenic mutation. These data reveal a synthetic lethality between inhibition of glutamate oxaloacetate transaminase and ACLY inhibition that is specific for KRas-driven cancer cells and the apparent metabolic reprogramming induced by activating mutations to KRas.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>36269753</pmid><doi>10.1371/journal.pone.0276579</doi><tpages>e0276579</tpages><orcidid>https://orcid.org/0000-0003-0900-6946</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adenosine diphosphate AKT protein Antibodies Apoptosis ATP ATP citrate lyase Biology and Life Sciences Breast cancer Cancer Cancer cells Cell cycle Cell death Cell metabolism Cell survival Cell viability Deprivation Endoplasmic reticulum Enzymes Fatty acids Fibroblasts Gene mutations Genetic aspects Glutamine Insulin K-Ras protein Ketoglutaric acid Kinases Lethality Lipids Lyases Medicine and Health Sciences Membranes Metabolism Mitochondria Mutation Oleic acid Oncology, Experimental Phosphatidic acid Phosphorylation Physical Sciences Physiological aspects Proteins Rapamycin Research and Analysis Methods Ribose Synthesis Telomerase reverse transcriptase TOR protein Transaminase Transaminases Tricarboxylic acid cycle |
| title | Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-17T04%3A04%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Inhibiting%20glutamine%20utilization%20creates%20a%20synthetic%20lethality%20for%20suppression%20of%20ATP%20citrate%20lyase%20in%20KRas-driven%20cancer%20cells&rft.jtitle=PloS%20one&rft.au=Hatipoglu,%20Ahmet&rft.date=2022-10-21&rft.volume=17&rft.issue=10&rft.spage=e0276579&rft.epage=e0276579&rft.pages=e0276579-e0276579&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0276579&rft_dat=%3Cgale_plos_%3EA723620629%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2727179119&rft_id=info:pmid/36269753&rft_galeid=A723620629&rft_doaj_id=oai_doaj_org_article_f1e75bd3e5584ca3baf10df019cae074&rfr_iscdi=true |