The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation
VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We fo...
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| Veröffentlicht in: | Oncogene 2019-04, Vol.38 (17), p.3216-3231 |
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| creator | Parzych, Katarzyna Saavedra-García, Paula Valbuena, Gabriel N. Al-Sadah, Hibah A. Robinson, Mark E. Penfold, Lucy Kuzeva, Desislava M. Ruiz-Tellez, Angie Loaiza, Sandra Holzmann, Viktoria Caputo, Valentina Johnson, David C. Kaiser, Martin F. Karadimitris, Anastasios Lam, Eric W-F Chevet, Eric Feldhahn, Niklas Keun, Hector C. Auner, Holger W. |
| description | VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis. |
| doi_str_mv | 10.1038/s41388-018-0651-z |
| format | Article |
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Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-018-0651-z</identifier><identifier>PMID: 30626938</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/106 ; 13/31 ; 13/89 ; 38/77 ; 631/337/474/582 ; 631/67/2327 ; 631/80/86/2369 ; 82 ; 82/58 ; 82/80 ; A549 Cells ; Adenosine Triphosphatases - metabolism ; Amino acids ; Antineoplastic agents ; Apoptosis ; Autophagy ; Autophagy - physiology ; Biochemistry ; Cancer ; Cancer cells ; Cell Biology ; Cell death ; Cell Line, Tumor ; Chemoreception ; Dosage and administration ; Drug therapy ; Extracellular signal-regulated kinase ; Gene expression ; Gene Expression - physiology ; Genes ; Genetic aspects ; Glucose ; Glucose - metabolism ; Glutamine ; Glutamine - metabolism ; Glycolysis ; Human Genetics ; Humans ; Internal Medicine ; Intracellular signalling ; Kinases ; Life Sciences ; MAP Kinase Signaling System - physiology ; MCF-7 Cells ; Medicine ; Medicine & Public Health ; Metabolism ; Metabolites ; Multiple myeloma ; Multiple Myeloma - metabolism ; Nuclear Proteins - metabolism ; Nutrients - metabolism ; Oncology ; PC-3 Cells ; Phagocytosis ; Protein Serine-Threonine Kinases - metabolism ; Proteins ; Proteolysis ; Proteostasis - physiology ; Signal Transduction - physiology ; Tumor cell lines ; Valosin Containing Protein - metabolism</subject><ispartof>Oncogene, 2019-04, Vol.38 (17), p.3216-3231</ispartof><rights>The Author(s) 2019</rights><rights>COPYRIGHT 2019 Nature Publishing Group</rights><rights>This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. 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Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Parzych, Katarzyna</au><au>Saavedra-García, Paula</au><au>Valbuena, Gabriel N.</au><au>Al-Sadah, Hibah A.</au><au>Robinson, Mark E.</au><au>Penfold, Lucy</au><au>Kuzeva, Desislava M.</au><au>Ruiz-Tellez, Angie</au><au>Loaiza, Sandra</au><au>Holzmann, Viktoria</au><au>Caputo, Valentina</au><au>Johnson, David C.</au><au>Kaiser, Martin F.</au><au>Karadimitris, Anastasios</au><au>Lam, Eric W-F</au><au>Chevet, Eric</au><au>Feldhahn, Niklas</au><au>Keun, Hector C.</au><au>Auner, Holger W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2019-04</date><risdate>2019</risdate><volume>38</volume><issue>17</issue><spage>3216</spage><epage>3231</epage><pages>3216-3231</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30626938</pmid><doi>10.1038/s41388-018-0651-z</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0003-4040-0642</orcidid><orcidid>https://orcid.org/0000-0003-0887-3343</orcidid><orcidid>https://orcid.org/0000-0003-0642-4165</orcidid><orcidid>https://orcid.org/0000-0002-9566-9780</orcidid><orcidid>https://orcid.org/0000-0001-6825-7214</orcidid><orcidid>https://orcid.org/0000-0003-1274-3576</orcidid><orcidid>https://orcid.org/0000-0001-5855-4522</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0950-9232 |
| ispartof | Oncogene, 2019-04, Vol.38 (17), p.3216-3231 |
| issn | 0950-9232 1476-5594 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6756015 |
| source | MEDLINE; Alma/SFX Local Collection |
| subjects | 13/106 13/31 13/89 38/77 631/337/474/582 631/67/2327 631/80/86/2369 82 82/58 82/80 A549 Cells Adenosine Triphosphatases - metabolism Amino acids Antineoplastic agents Apoptosis Autophagy Autophagy - physiology Biochemistry Cancer Cancer cells Cell Biology Cell death Cell Line, Tumor Chemoreception Dosage and administration Drug therapy Extracellular signal-regulated kinase Gene expression Gene Expression - physiology Genes Genetic aspects Glucose Glucose - metabolism Glutamine Glutamine - metabolism Glycolysis Human Genetics Humans Internal Medicine Intracellular signalling Kinases Life Sciences MAP Kinase Signaling System - physiology MCF-7 Cells Medicine Medicine & Public Health Metabolism Metabolites Multiple myeloma Multiple Myeloma - metabolism Nuclear Proteins - metabolism Nutrients - metabolism Oncology PC-3 Cells Phagocytosis Protein Serine-Threonine Kinases - metabolism Proteins Proteolysis Proteostasis - physiology Signal Transduction - physiology Tumor cell lines Valosin Containing Protein - metabolism |
| title | The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T21%3A17%3A16IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20coordinated%20action%20of%20VCP/p97%20and%20GCN2%20regulates%20cancer%20cell%20metabolism%20and%20proteostasis%20during%20nutrient%20limitation&rft.jtitle=Oncogene&rft.au=Parzych,%20Katarzyna&rft.date=2019-04&rft.volume=38&rft.issue=17&rft.spage=3216&rft.epage=3231&rft.pages=3216-3231&rft.issn=0950-9232&rft.eissn=1476-5594&rft_id=info:doi/10.1038/s41388-018-0651-z&rft_dat=%3Cgale_pubme%3EA583628631%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2214989892&rft_id=info:pmid/30626938&rft_galeid=A583628631&rfr_iscdi=true |