Macropinocytosis confers resistance to therapies targeting cancer anabolism
Identifieur interne : 000F80 ( Ncbi/Merge ); précédent : 000F79; suivant : 000F81Macropinocytosis confers resistance to therapies targeting cancer anabolism
Auteurs : Vaishali Jayashankar ; Aimee L. EdingerSource :
- Nature Communications [ 2041-1723 ] ; 2020.
Abstract
Macropinocytic cancer cells scavenge amino acids from extracellular proteins. Here, we show that consuming necrotic cell debris via macropinocytosis (necrocytosis) offers additional anabolic benefits. A click chemistry-based flux assay reveals that necrocytosis provides not only amino acids, but sugars, fatty acids and nucleotides for biosynthesis, conferring resistance to therapies targeting anabolic pathways. Indeed, necrotic cell debris allow macropinocytic breast and prostate cancer cells to proliferate, despite fatty acid synthase inhibition. Standard therapies such as gemcitabine, 5-fluorouracil (5-FU), doxorubicin and gamma-irradiation directly or indirectly target nucleotide biosynthesis, creating stress that is relieved by scavenged nucleotides. Strikingly, necrotic debris also render macropinocytic, but not non-macropinocytic, pancreas and breast cancer cells resistant to these treatments. Selective, genetic inhibition of macropinocytosis confirms that necrocytosis both supports tumor growth and limits the effectiveness of 5-FU in vivo. Therefore, this study establishes necrocytosis as a mechanism for drug resistance.
Url:
DOI: 10.1038/s41467-020-14928-3
PubMed: 32111826
PubMed Central: 7048872
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Macropinocytosis confers resistance to therapies targeting cancer anabolism</title><author><name sortKey="Jayashankar, Vaishali" sort="Jayashankar, Vaishali" uniqKey="Jayashankar V" first="Vaishali" last="Jayashankar">Vaishali Jayashankar</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Edinger, Aimee L" sort="Edinger, Aimee L" uniqKey="Edinger A" first="Aimee L." last="Edinger">Aimee L. Edinger</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32111826</idno><idno type="pmc">7048872</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048872</idno><idno type="RBID">PMC:7048872</idno><idno type="doi">10.1038/s41467-020-14928-3</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000155</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000155</idno><idno type="wicri:Area/Pmc/Curation">000155</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000155</idno><idno type="wicri:Area/Pmc/Checkpoint">000110</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000110</idno><idno type="wicri:Area/Ncbi/Merge">000F80</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Macropinocytosis confers resistance to therapies targeting cancer anabolism</title><author><name sortKey="Jayashankar, Vaishali" sort="Jayashankar, Vaishali" uniqKey="Jayashankar V" first="Vaishali" last="Jayashankar">Vaishali Jayashankar</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Edinger, Aimee L" sort="Edinger, Aimee L" uniqKey="Edinger A" first="Aimee L." last="Edinger">Aimee L. Edinger</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Macropinocytic cancer cells scavenge amino acids from extracellular proteins. Here, we show that consuming necrotic cell debris via macropinocytosis (necrocytosis) offers additional anabolic benefits. A click chemistry-based flux assay reveals that necrocytosis provides not only amino acids, but sugars, fatty acids and nucleotides for biosynthesis, conferring resistance to therapies targeting anabolic pathways. Indeed, necrotic cell debris allow macropinocytic breast and prostate cancer cells to proliferate, despite fatty acid synthase inhibition. Standard therapies such as gemcitabine, 5-fluorouracil (5-FU), doxorubicin and gamma-irradiation directly or indirectly target nucleotide biosynthesis, creating stress that is relieved by scavenged nucleotides. Strikingly, necrotic debris also render macropinocytic, but not non-macropinocytic, pancreas and breast cancer cells resistant to these treatments. Selective, genetic inhibition of macropinocytosis confirms that necrocytosis both supports tumor growth and limits the effectiveness of 5-FU in vivo. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id><journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id><journal-title-group><journal-title>Nature Communications</journal-title></journal-title-group><issn pub-type="epub">2041-1723</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32111826</article-id><article-id pub-id-type="pmc">7048872</article-id><article-id pub-id-type="publisher-id">14928</article-id><article-id pub-id-type="doi">10.1038/s41467-020-14928-3</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Macropinocytosis confers resistance to therapies targeting cancer anabolism</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Jayashankar</surname><given-names>Vaishali</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Edinger</surname><given-names>Aimee L.</given-names></name><address><email>aedinger@uci.edu</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0668 7243</institution-id><institution-id institution-id-type="GRID">grid.266093.8</institution-id><institution>Department of Developmental and Cell Biology,</institution><institution>University of California Irvine,</institution></institution-wrap>Irvine, CA 92697 USA</aff></contrib-group><pub-date pub-type="epub"><day>28</day><month>2</month><year>2020</year></pub-date><pub-date pub-type="pmc-release"><day>28</day><month>2</month><year>2020</year></pub-date><pub-date pub-type="collection"><year>2020</year></pub-date><volume>11</volume><elocation-id>1121</elocation-id><history><date date-type="received"><day>29</day><month>3</month><year>2019</year></date><date date-type="accepted"><day>6</day><month>2</month><year>2020</year></date></history><permissions><copyright-statement>© The Author(s) 2020</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">Macropinocytic cancer cells scavenge amino acids from extracellular proteins. Here, we show that consuming necrotic cell debris via macropinocytosis (necrocytosis) offers additional anabolic benefits. A click chemistry-based flux assay reveals that necrocytosis provides not only amino acids, but sugars, fatty acids and nucleotides for biosynthesis, conferring resistance to therapies targeting anabolic pathways. Indeed, necrotic cell debris allow macropinocytic breast and prostate cancer cells to proliferate, despite fatty acid synthase inhibition. Standard therapies such as gemcitabine, 5-fluorouracil (5-FU), doxorubicin and gamma-irradiation directly or indirectly target nucleotide biosynthesis, creating stress that is relieved by scavenged nucleotides. Strikingly, necrotic debris also render macropinocytic, but not non-macropinocytic, pancreas and breast cancer cells resistant to these treatments. Selective, genetic inhibition of macropinocytosis confirms that necrocytosis both supports tumor growth and limits the effectiveness of 5-FU in vivo. Therefore, this study establishes necrocytosis as a mechanism for drug resistance.</p></abstract><abstract id="Abs2" abstract-type="web-summary"><p id="Par2">Macropinocytosis allows cancer cells to cope with nutrient stress. Here, the authors use a selective, genetic approach to inhibit macropinocytosis and show that consuming necrotic cell debris via macropinocytosis—necrocytosis—affords resistance to many therapies that target biosynthesis.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Breast cancer</kwd><kwd>Cancer metabolism</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2020</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list></list><tree><noCountry><name sortKey="Edinger, Aimee L" sort="Edinger, Aimee L" uniqKey="Edinger A" first="Aimee L." last="Edinger">Aimee L. Edinger</name><name sortKey="Jayashankar, Vaishali" sort="Jayashankar, Vaishali" uniqKey="Jayashankar V" first="Vaishali" last="Jayashankar">Vaishali Jayashankar</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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