Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer
Lien et al. show that oncogenic PI(3)K/Akt signalling stimulates glutathione (GSH) synthesis by activation of the transcription factor Nrf2 and regulation of GSH biosynthesis genes in breast cancer. Cancer cells often select for mutations that enhance signalling through pathways that promote anabol...
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| Veröffentlicht in: | Nature cell biology 2016-05, Vol.18 (5), p.572-578 |
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| creator | Lien, Evan C. Lyssiotis, Costas A. Juvekar, Ashish Hu, Hai Asara, John M. Cantley, Lewis C. Toker, Alex |
| description | Lien
et al.
show that oncogenic PI(3)K/Akt signalling stimulates glutathione (GSH) synthesis by activation of the transcription factor Nrf2 and regulation of GSH biosynthesis genes in breast cancer.
Cancer cells often select for mutations that enhance signalling through pathways that promote anabolic metabolism
1
. Although the PI(3)K/Akt signalling pathway, which is frequently dysregulated in breast cancer
2
, is a well-established regulator of central glucose metabolism and aerobic glycolysis
3
,
4
, its regulation of other metabolic processes required for tumour growth is not well defined. Here we report that in mammary epithelial cells, oncogenic PI(3)K/Akt stimulates glutathione (GSH) biosynthesis by stabilizing and activating NRF2 to upregulate the GSH biosynthetic genes. Increased NRF2 stability is dependent on the Akt-mediated accumulation of p21
Cip1/WAF1
and GSK-3β inhibition. Consistently, in human breast tumours, upregulation of NRF2 targets is associated with PI(3)K pathway mutation status and oncogenic Akt activation. Elevated GSH biosynthesis is required for PI(3)K/Akt-driven resistance to oxidative stress, initiation of tumour spheroids, and anchorage-independent growth. Furthermore, inhibition of GSH biosynthesis with buthionine sulfoximine synergizes with cisplatin to selectively induce tumour regression in PI(3)K pathway mutant breast cancer cells, both
in vitro
and
in vivo
. Our findings provide insight into GSH biosynthesis as a metabolic vulnerability associated with PI(3)K pathway mutant breast cancers. |
| doi_str_mv | 10.1038/ncb3341 |
| format | Article |
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et al.
show that oncogenic PI(3)K/Akt signalling stimulates glutathione (GSH) synthesis by activation of the transcription factor Nrf2 and regulation of GSH biosynthesis genes in breast cancer.
Cancer cells often select for mutations that enhance signalling through pathways that promote anabolic metabolism
1
. Although the PI(3)K/Akt signalling pathway, which is frequently dysregulated in breast cancer
2
, is a well-established regulator of central glucose metabolism and aerobic glycolysis
3
,
4
, its regulation of other metabolic processes required for tumour growth is not well defined. Here we report that in mammary epithelial cells, oncogenic PI(3)K/Akt stimulates glutathione (GSH) biosynthesis by stabilizing and activating NRF2 to upregulate the GSH biosynthetic genes. Increased NRF2 stability is dependent on the Akt-mediated accumulation of p21
Cip1/WAF1
and GSK-3β inhibition. Consistently, in human breast tumours, upregulation of NRF2 targets is associated with PI(3)K pathway mutation status and oncogenic Akt activation. Elevated GSH biosynthesis is required for PI(3)K/Akt-driven resistance to oxidative stress, initiation of tumour spheroids, and anchorage-independent growth. Furthermore, inhibition of GSH biosynthesis with buthionine sulfoximine synergizes with cisplatin to selectively induce tumour regression in PI(3)K pathway mutant breast cancer cells, both
in vitro
and
in vivo
. Our findings provide insight into GSH biosynthesis as a metabolic vulnerability associated with PI(3)K pathway mutant breast cancers.</description><identifier>ISSN: 1465-7392</identifier><identifier>EISSN: 1476-4679</identifier><identifier>DOI: 10.1038/ncb3341</identifier><identifier>PMID: 27088857</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/106 ; 13/2 ; 13/31 ; 13/89 ; 13/95 ; 14/63 ; 38/39 ; 38/44 ; 38/70 ; 38/88 ; 45/90 ; 631/67 ; 631/67/2327 ; 631/80/86 ; 64/60 ; 82/29 ; 82/58 ; 96/95 ; Biosynthesis ; Biosynthetic Pathways - genetics ; Breast cancer ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Buthionine Sulfoximine - pharmacology ; Cancer Research ; Cell Biology ; Cell Line, Tumor ; Cisplatin - pharmacology ; Developmental Biology ; Female ; Glutathione - biosynthesis ; Growth factors ; Humans ; Kinases ; letter ; Life Sciences ; Medical research ; Medical schools ; Metabolism ; Metabolites ; Mutation ; Mutation - genetics ; NF-E2-Related Factor 2 - metabolism ; Oxidative stress ; Oxidative Stress - drug effects ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt - metabolism ; Signal Transduction - drug effects ; Spheroids, Cellular - metabolism ; Spheroids, Cellular - pathology ; Stem Cells ; Tumors</subject><ispartof>Nature cell biology, 2016-05, Vol.18 (5), p.572-578</ispartof><rights>Springer Nature Limited 2016</rights><rights>Copyright Nature Publishing Group May 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-55105f922b043d1c3911813fef3d146401172247513e0d257ff98e7a24beb27f3</citedby><cites>FETCH-LOGICAL-c441t-55105f922b043d1c3911813fef3d146401172247513e0d257ff98e7a24beb27f3</cites><orcidid>0000-0001-9309-6141</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,27933,27934</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27088857$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lien, Evan C.</creatorcontrib><creatorcontrib>Lyssiotis, Costas A.</creatorcontrib><creatorcontrib>Juvekar, Ashish</creatorcontrib><creatorcontrib>Hu, Hai</creatorcontrib><creatorcontrib>Asara, John M.</creatorcontrib><creatorcontrib>Cantley, Lewis C.</creatorcontrib><creatorcontrib>Toker, Alex</creatorcontrib><title>Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer</title><title>Nature cell biology</title><addtitle>Nat Cell Biol</addtitle><addtitle>Nat Cell Biol</addtitle><description>Lien
et al.
show that oncogenic PI(3)K/Akt signalling stimulates glutathione (GSH) synthesis by activation of the transcription factor Nrf2 and regulation of GSH biosynthesis genes in breast cancer.
Cancer cells often select for mutations that enhance signalling through pathways that promote anabolic metabolism
1
. Although the PI(3)K/Akt signalling pathway, which is frequently dysregulated in breast cancer
2
, is a well-established regulator of central glucose metabolism and aerobic glycolysis
3
,
4
, its regulation of other metabolic processes required for tumour growth is not well defined. Here we report that in mammary epithelial cells, oncogenic PI(3)K/Akt stimulates glutathione (GSH) biosynthesis by stabilizing and activating NRF2 to upregulate the GSH biosynthetic genes. Increased NRF2 stability is dependent on the Akt-mediated accumulation of p21
Cip1/WAF1
and GSK-3β inhibition. Consistently, in human breast tumours, upregulation of NRF2 targets is associated with PI(3)K pathway mutation status and oncogenic Akt activation. Elevated GSH biosynthesis is required for PI(3)K/Akt-driven resistance to oxidative stress, initiation of tumour spheroids, and anchorage-independent growth. Furthermore, inhibition of GSH biosynthesis with buthionine sulfoximine synergizes with cisplatin to selectively induce tumour regression in PI(3)K pathway mutant breast cancer cells, both
in vitro
and
in vivo
. Our findings provide insight into GSH biosynthesis as a metabolic vulnerability associated with PI(3)K pathway mutant breast cancers.</description><subject>13/1</subject><subject>13/106</subject><subject>13/2</subject><subject>13/31</subject><subject>13/89</subject><subject>13/95</subject><subject>14/63</subject><subject>38/39</subject><subject>38/44</subject><subject>38/70</subject><subject>38/88</subject><subject>45/90</subject><subject>631/67</subject><subject>631/67/2327</subject><subject>631/80/86</subject><subject>64/60</subject><subject>82/29</subject><subject>82/58</subject><subject>96/95</subject><subject>Biosynthesis</subject><subject>Biosynthetic Pathways - genetics</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Buthionine Sulfoximine - pharmacology</subject><subject>Cancer Research</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cisplatin - pharmacology</subject><subject>Developmental Biology</subject><subject>Female</subject><subject>Glutathione - biosynthesis</subject><subject>Growth factors</subject><subject>Humans</subject><subject>Kinases</subject><subject>letter</subject><subject>Life Sciences</subject><subject>Medical research</subject><subject>Medical schools</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Mutation</subject><subject>Mutation - genetics</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphorylation</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Spheroids, Cellular - metabolism</subject><subject>Spheroids, Cellular - pathology</subject><subject>Stem Cells</subject><subject>Tumors</subject><issn>1465-7392</issn><issn>1476-4679</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNpdkFtLw0AQhRdRrDf8BxLwQX2I3dlLNnksxRsW9EHBt7CbTnRrutHdjdB_b0rrhcLAzDAf5wyHkGOgl0B5PnSV4VzAFtkDobJUZKrYXs6ZTBUv2IDshzCjFISgapcMmKJ5nku1R15umi7q-GZbh4mxbVi4-IbBhqQvncwxatM2tkq-usah18Y2Ni4S65LHu3N-cT8cvcd06u0XusR41CEmlXYV-kOyU-sm4NG6H5Dn66un8W06ebi5G48maSUExFRKoLIuGDNU8ClUvADIgddY95vIBAVQjAklgSOdMqnqushRaSYMGqZqfkDOV7ofvv3sMMRybkOFTaMdtl0oQeWSgaTAevR0A521nXf9d0uq91Aiy3rqbEVVvg3BY11-eDvXflECLZdhl-uwe_JkrdeZOU5_uZ90_34L_cm9ov9nuKH1Dbg8hP8</recordid><startdate>20160501</startdate><enddate>20160501</enddate><creator>Lien, Evan C.</creator><creator>Lyssiotis, Costas A.</creator><creator>Juvekar, Ashish</creator><creator>Hu, Hai</creator><creator>Asara, John M.</creator><creator>Cantley, Lewis C.</creator><creator>Toker, Alex</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-9309-6141</orcidid></search><sort><creationdate>20160501</creationdate><title>Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer</title><author>Lien, Evan C. ; Lyssiotis, Costas A. ; Juvekar, Ashish ; Hu, Hai ; Asara, John M. ; Cantley, Lewis C. ; Toker, Alex</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c441t-55105f922b043d1c3911813fef3d146401172247513e0d257ff98e7a24beb27f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>13/1</topic><topic>13/106</topic><topic>13/2</topic><topic>13/31</topic><topic>13/89</topic><topic>13/95</topic><topic>14/63</topic><topic>38/39</topic><topic>38/44</topic><topic>38/70</topic><topic>38/88</topic><topic>45/90</topic><topic>631/67</topic><topic>631/67/2327</topic><topic>631/80/86</topic><topic>64/60</topic><topic>82/29</topic><topic>82/58</topic><topic>96/95</topic><topic>Biosynthesis</topic><topic>Biosynthetic Pathways - 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metabolism</topic><topic>Spheroids, Cellular - pathology</topic><topic>Stem Cells</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lien, Evan C.</creatorcontrib><creatorcontrib>Lyssiotis, Costas A.</creatorcontrib><creatorcontrib>Juvekar, Ashish</creatorcontrib><creatorcontrib>Hu, Hai</creatorcontrib><creatorcontrib>Asara, John M.</creatorcontrib><creatorcontrib>Cantley, Lewis C.</creatorcontrib><creatorcontrib>Toker, Alex</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Nature cell biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lien, Evan C.</au><au>Lyssiotis, Costas A.</au><au>Juvekar, Ashish</au><au>Hu, Hai</au><au>Asara, John M.</au><au>Cantley, Lewis C.</au><au>Toker, Alex</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer</atitle><jtitle>Nature cell biology</jtitle><stitle>Nat Cell Biol</stitle><addtitle>Nat Cell Biol</addtitle><date>2016-05-01</date><risdate>2016</risdate><volume>18</volume><issue>5</issue><spage>572</spage><epage>578</epage><pages>572-578</pages><issn>1465-7392</issn><eissn>1476-4679</eissn><abstract>Lien
et al.
show that oncogenic PI(3)K/Akt signalling stimulates glutathione (GSH) synthesis by activation of the transcription factor Nrf2 and regulation of GSH biosynthesis genes in breast cancer.
Cancer cells often select for mutations that enhance signalling through pathways that promote anabolic metabolism
1
. Although the PI(3)K/Akt signalling pathway, which is frequently dysregulated in breast cancer
2
, is a well-established regulator of central glucose metabolism and aerobic glycolysis
3
,
4
, its regulation of other metabolic processes required for tumour growth is not well defined. Here we report that in mammary epithelial cells, oncogenic PI(3)K/Akt stimulates glutathione (GSH) biosynthesis by stabilizing and activating NRF2 to upregulate the GSH biosynthetic genes. Increased NRF2 stability is dependent on the Akt-mediated accumulation of p21
Cip1/WAF1
and GSK-3β inhibition. Consistently, in human breast tumours, upregulation of NRF2 targets is associated with PI(3)K pathway mutation status and oncogenic Akt activation. Elevated GSH biosynthesis is required for PI(3)K/Akt-driven resistance to oxidative stress, initiation of tumour spheroids, and anchorage-independent growth. Furthermore, inhibition of GSH biosynthesis with buthionine sulfoximine synergizes with cisplatin to selectively induce tumour regression in PI(3)K pathway mutant breast cancer cells, both
in vitro
and
in vivo
. Our findings provide insight into GSH biosynthesis as a metabolic vulnerability associated with PI(3)K pathway mutant breast cancers.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27088857</pmid><doi>10.1038/ncb3341</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0001-9309-6141</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13/1 13/106 13/2 13/31 13/89 13/95 14/63 38/39 38/44 38/70 38/88 45/90 631/67 631/67/2327 631/80/86 64/60 82/29 82/58 96/95 Biosynthesis Biosynthetic Pathways - genetics Breast cancer Breast Neoplasms - metabolism Breast Neoplasms - pathology Buthionine Sulfoximine - pharmacology Cancer Research Cell Biology Cell Line, Tumor Cisplatin - pharmacology Developmental Biology Female Glutathione - biosynthesis Growth factors Humans Kinases letter Life Sciences Medical research Medical schools Metabolism Metabolites Mutation Mutation - genetics NF-E2-Related Factor 2 - metabolism Oxidative stress Oxidative Stress - drug effects Phosphatidylinositol 3-Kinases - metabolism Phosphorylation Proto-Oncogene Proteins c-akt - metabolism Signal Transduction - drug effects Spheroids, Cellular - metabolism Spheroids, Cellular - pathology Stem Cells Tumors |
| title | Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer |
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