Inhibition of PI3K/Akt/mTOR signaling in PI3KR2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis.
Identifieur interne : 000808 ( Main/Exploration ); précédent : 000807; suivant : 000809Inhibition of PI3K/Akt/mTOR signaling in PI3KR2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis.
Auteurs : Sugong Chen [États-Unis] ; Robert C. Fisher [États-Unis] ; Steven Signs [États-Unis] ; L Alex Molina [États-Unis] ; Anitha K. Shenoy [États-Unis] ; Maria-Cecilia Lopez [États-Unis] ; Henry V. Baker [États-Unis] ; John M. Koomen [États-Unis] ; Yi Chen [États-Unis] ; Haley Gittleman [États-Unis] ; Jill Barnholtz-Sloan [États-Unis] ; Annamarie Berg [États-Unis] ; Henry D. Appelman [États-Unis] ; Emina H. Huang [États-Unis]Source :
- Oncotarget [ 1949-2553 ] ; 2017.
Abstract
In sporadic colon cancer, colon cancer stem cells (CCSCs) initiate tumorigenesis and may contribute to late disease recurrences and metastases. We previously showed that aldehyde dehydrogenase (ALDH) activity (as indicated by the ALDEFLUOR® assay) is an effective marker for highly enriching CCSCs for further evaluation. Here, we used comparative transcriptome and proteome approaches to identify signaling pathways overrepresented in the CCSC population. We found overexpression of several components of the phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway, including PI3KR2, a regulatory subunit of PI3K. LY294002, a PI3K inhibitor, defined the contribution of the PI3K/Akt/mTOR signaling pathway in CCSCs. LY294002-treated CCSCs showed decreases in proliferation, sphere formation and self-renewal, in phosphorylation-dependent activation of Akt, and in expression of cyclin D1. Inhibition of PI3K in vivo reduced tumorigenicity, increased detection of cleaved caspase 3, an indicator of apoptosis, and elevated expression of the inflammatory chemokine, CXCL8. Collectively, these results indicate that PI3K/Akt/mTOR signaling controls CCSC proliferation and CCSC survival, and suggests that it would be useful to develop therapeutic agents that target this signaling pathway.
DOI: 10.18632/oncotarget.9919
PubMed: 28881576
PubMed Central: PMC5584153
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Inhibition of PI3K/Akt/mTOR signaling in PI3KR2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis.</title><author><name sortKey="Chen, Sugong" sort="Chen, Sugong" uniqKey="Chen S" first="Sugong" last="Chen">Sugong Chen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Surgery, University of Florida, Gainesville, Florida 32610, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Surgery, University of Florida, Gainesville, Florida 32610</wicri:regionArea><wicri:noRegion>Florida 32610</wicri:noRegion></affiliation></author><author><name sortKey="Fisher, Robert C" sort="Fisher, Robert C" uniqKey="Fisher R" first="Robert C" last="Fisher">Robert C. Fisher</name><affiliation wicri:level="1"><nlm:affiliation>Department of Surgery, University of Florida, Gainesville, Florida 32610, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Surgery, University of Florida, Gainesville, Florida 32610</wicri:regionArea><wicri:noRegion>Florida 32610</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195</wicri:regionArea><wicri:noRegion>Ohio 44195</wicri:noRegion></affiliation></author><author><name sortKey="Signs, Steven" sort="Signs, Steven" uniqKey="Signs S" first="Steven" last="Signs">Steven Signs</name><affiliation wicri:level="1"><nlm:affiliation>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195</wicri:regionArea><wicri:noRegion>Ohio 44195</wicri:noRegion></affiliation></author><author><name sortKey="Molina, L Alex" sort="Molina, L Alex" uniqKey="Molina L" first="L Alex" last="Molina">L Alex Molina</name><affiliation wicri:level="1"><nlm:affiliation>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195</wicri:regionArea><wicri:noRegion>Ohio 44195</wicri:noRegion></affiliation></author><author><name sortKey="Shenoy, Anitha K" sort="Shenoy, Anitha K" uniqKey="Shenoy A" first="Anitha K" last="Shenoy">Anitha K. 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Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612</wicri:regionArea><wicri:noRegion>Florida 33612</wicri:noRegion></affiliation></author><author><name sortKey="Gittleman, Haley" sort="Gittleman, Haley" uniqKey="Gittleman H" first="Haley" last="Gittleman">Haley Gittleman</name><affiliation wicri:level="1"><nlm:affiliation>Bioinformatics, Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Bioinformatics, Case Comprehensive Cancer Center, Cleveland, Ohio 44106</wicri:regionArea><wicri:noRegion>Ohio 44106</wicri:noRegion></affiliation></author><author><name sortKey="Barnholtz Sloan, Jill" sort="Barnholtz Sloan, Jill" uniqKey="Barnholtz Sloan J" first="Jill" last="Barnholtz-Sloan">Jill Barnholtz-Sloan</name><affiliation wicri:level="1"><nlm:affiliation>Bioinformatics, Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Bioinformatics, Case Comprehensive Cancer Center, Cleveland, Ohio 44106</wicri:regionArea><wicri:noRegion>Ohio 44106</wicri:noRegion></affiliation></author><author><name sortKey="Berg, Annamarie" sort="Berg, Annamarie" uniqKey="Berg A" first="Annamarie" last="Berg">Annamarie Berg</name><affiliation wicri:level="1"><nlm:affiliation>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195</wicri:regionArea><wicri:noRegion>Ohio 44195</wicri:noRegion></affiliation></author><author><name sortKey="Appelman, Henry D" sort="Appelman, Henry D" uniqKey="Appelman H" first="Henry D" last="Appelman">Henry D. 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Fisher</name><affiliation wicri:level="1"><nlm:affiliation>Department of Surgery, University of Florida, Gainesville, Florida 32610, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Surgery, University of Florida, Gainesville, Florida 32610</wicri:regionArea><wicri:noRegion>Florida 32610</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195</wicri:regionArea><wicri:noRegion>Ohio 44195</wicri:noRegion></affiliation></author><author><name sortKey="Signs, Steven" sort="Signs, Steven" uniqKey="Signs S" first="Steven" last="Signs">Steven Signs</name><affiliation wicri:level="1"><nlm:affiliation>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195</wicri:regionArea><wicri:noRegion>Ohio 44195</wicri:noRegion></affiliation></author><author><name sortKey="Molina, L Alex" sort="Molina, L Alex" uniqKey="Molina L" first="L Alex" last="Molina">L Alex Molina</name><affiliation wicri:level="1"><nlm:affiliation>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195</wicri:regionArea><wicri:noRegion>Ohio 44195</wicri:noRegion></affiliation></author><author><name sortKey="Shenoy, Anitha K" sort="Shenoy, Anitha K" uniqKey="Shenoy A" first="Anitha K" last="Shenoy">Anitha K. Shenoy</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610</wicri:regionArea><wicri:noRegion>Florida 32610</wicri:noRegion></affiliation></author><author><name sortKey="Lopez, Maria Cecilia" sort="Lopez, Maria Cecilia" uniqKey="Lopez M" first="Maria-Cecilia" last="Lopez">Maria-Cecilia Lopez</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610</wicri:regionArea><wicri:noRegion>Florida 32610</wicri:noRegion></affiliation></author><author><name sortKey="Baker, Henry V" sort="Baker, Henry V" uniqKey="Baker H" first="Henry V" last="Baker">Henry V. Baker</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610</wicri:regionArea><wicri:noRegion>Florida 32610</wicri:noRegion></affiliation></author><author><name sortKey="Koomen, John M" sort="Koomen, John M" uniqKey="Koomen J" first="John M" last="Koomen">John M. Koomen</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Oncology and Proteomics, SRB3, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Oncology and Proteomics, SRB3, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612</wicri:regionArea><wicri:noRegion>Florida 33612</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Yi" sort="Chen, Yi" uniqKey="Chen Y" first="Yi" last="Chen">Yi Chen</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Oncology and Proteomics, SRB3, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Oncology and Proteomics, SRB3, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612</wicri:regionArea><wicri:noRegion>Florida 33612</wicri:noRegion></affiliation></author><author><name sortKey="Gittleman, Haley" sort="Gittleman, Haley" uniqKey="Gittleman H" first="Haley" last="Gittleman">Haley Gittleman</name><affiliation wicri:level="1"><nlm:affiliation>Bioinformatics, Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Bioinformatics, Case Comprehensive Cancer Center, Cleveland, Ohio 44106</wicri:regionArea><wicri:noRegion>Ohio 44106</wicri:noRegion></affiliation></author><author><name sortKey="Barnholtz Sloan, Jill" sort="Barnholtz Sloan, Jill" uniqKey="Barnholtz Sloan J" first="Jill" last="Barnholtz-Sloan">Jill Barnholtz-Sloan</name><affiliation wicri:level="1"><nlm:affiliation>Bioinformatics, Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Bioinformatics, Case Comprehensive Cancer Center, Cleveland, Ohio 44106</wicri:regionArea><wicri:noRegion>Ohio 44106</wicri:noRegion></affiliation></author><author><name sortKey="Berg, Annamarie" sort="Berg, Annamarie" uniqKey="Berg A" first="Annamarie" last="Berg">Annamarie Berg</name><affiliation wicri:level="1"><nlm:affiliation>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195</wicri:regionArea><wicri:noRegion>Ohio 44195</wicri:noRegion></affiliation></author><author><name sortKey="Appelman, Henry D" sort="Appelman, Henry D" uniqKey="Appelman H" first="Henry D" last="Appelman">Henry D. Appelman</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109</wicri:regionArea><wicri:noRegion>Michigan 48109</wicri:noRegion></affiliation></author><author><name sortKey="Huang, Emina H" sort="Huang, Emina H" uniqKey="Huang E" first="Emina H" last="Huang">Emina H. Huang</name><affiliation wicri:level="1"><nlm:affiliation>Department of Surgery, University of Florida, Gainesville, Florida 32610, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Surgery, University of Florida, Gainesville, Florida 32610</wicri:regionArea><wicri:noRegion>Florida 32610</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195</wicri:regionArea><wicri:noRegion>Ohio 44195</wicri:noRegion></affiliation></author></analytic><series><title level="j">Oncotarget</title><idno type="eISSN">1949-2553</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">In sporadic colon cancer, colon cancer stem cells (CCSCs) initiate tumorigenesis and may contribute to late disease recurrences and metastases. We previously showed that aldehyde dehydrogenase (ALDH) activity (as indicated by the ALDEFLUOR<sup>®</sup> assay) is an effective marker for highly enriching CCSCs for further evaluation. Here, we used comparative transcriptome and proteome approaches to identify signaling pathways overrepresented in the CCSC population. We found overexpression of several components of the phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway, including PI3KR2, a regulatory subunit of PI3K. LY294002, a PI3K inhibitor, defined the contribution of the PI3K/Akt/mTOR signaling pathway in CCSCs. LY294002-treated CCSCs showed decreases in proliferation, sphere formation and self-renewal, in phosphorylation-dependent activation of Akt, and in expression of cyclin D1. Inhibition of PI3K <i>in vivo</i> reduced tumorigenicity, increased detection of cleaved caspase 3, an indicator of apoptosis, and elevated expression of the inflammatory chemokine, CXCL8. Collectively, these results indicate that PI3K/Akt/mTOR signaling controls CCSC proliferation and CCSC survival, and suggests that it would be useful to develop therapeutic agents that target this signaling pathway.</div></front></TEI><pubmed><MedlineCitation Status="PubMed-not-MEDLINE" Owner="NLM"><PMID Version="1">28881576</PMID><DateCompleted><Year>2017</Year><Month>09</Month><Day>25</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Electronic">1949-2553</ISSN><JournalIssue CitedMedium="Internet"><Volume>8</Volume><Issue>31</Issue><PubDate><Year>2017</Year><Month>Aug</Month><Day>01</Day></PubDate></JournalIssue><Title>Oncotarget</Title><ISOAbbreviation>Oncotarget</ISOAbbreviation></Journal><ArticleTitle>Inhibition of PI3K/Akt/mTOR signaling in PI3KR2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis.</ArticleTitle><Pagination><MedlinePgn>50476-50488</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.18632/oncotarget.9919</ELocationID><Abstract><AbstractText>In sporadic colon cancer, colon cancer stem cells (CCSCs) initiate tumorigenesis and may contribute to late disease recurrences and metastases. We previously showed that aldehyde dehydrogenase (ALDH) activity (as indicated by the ALDEFLUOR<sup>®</sup> assay) is an effective marker for highly enriching CCSCs for further evaluation. Here, we used comparative transcriptome and proteome approaches to identify signaling pathways overrepresented in the CCSC population. We found overexpression of several components of the phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway, including PI3KR2, a regulatory subunit of PI3K. LY294002, a PI3K inhibitor, defined the contribution of the PI3K/Akt/mTOR signaling pathway in CCSCs. LY294002-treated CCSCs showed decreases in proliferation, sphere formation and self-renewal, in phosphorylation-dependent activation of Akt, and in expression of cyclin D1. Inhibition of PI3K <i>in vivo</i> reduced tumorigenicity, increased detection of cleaved caspase 3, an indicator of apoptosis, and elevated expression of the inflammatory chemokine, CXCL8. Collectively, these results indicate that PI3K/Akt/mTOR signaling controls CCSC proliferation and CCSC survival, and suggests that it would be useful to develop therapeutic agents that target this signaling pathway.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y" EqualContrib="Y"><LastName>Chen</LastName><ForeName>Sugong</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Surgery, University of Florida, Gainesville, Florida 32610, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y" EqualContrib="Y"><LastName>Fisher</LastName><ForeName>Robert C</ForeName><Initials>RC</Initials><AffiliationInfo><Affiliation>Department of Surgery, University of Florida, Gainesville, Florida 32610, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Signs</LastName><ForeName>Steven</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Molina</LastName><ForeName>L Alex</ForeName><Initials>LA</Initials><AffiliationInfo><Affiliation>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shenoy</LastName><ForeName>Anitha K</ForeName><Initials>AK</Initials><AffiliationInfo><Affiliation>Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lopez</LastName><ForeName>Maria-Cecilia</ForeName><Initials>MC</Initials><AffiliationInfo><Affiliation>Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Baker</LastName><ForeName>Henry V</ForeName><Initials>HV</Initials><AffiliationInfo><Affiliation>Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Koomen</LastName><ForeName>John M</ForeName><Initials>JM</Initials><AffiliationInfo><Affiliation>Molecular Oncology and Proteomics, SRB3, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chen</LastName><ForeName>Yi</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Molecular Oncology and Proteomics, SRB3, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gittleman</LastName><ForeName>Haley</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Bioinformatics, Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Barnholtz-Sloan</LastName><ForeName>Jill</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Bioinformatics, Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Berg</LastName><ForeName>Annamarie</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Appelman</LastName><ForeName>Henry D</ForeName><Initials>HD</Initials><AffiliationInfo><Affiliation>Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Huang</LastName><ForeName>Emina H</ForeName><Initials>EH</Initials><AffiliationInfo><Affiliation>Department of Surgery, University of Florida, Gainesville, Florida 32610, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>U54 GM062119</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 CA157663</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 CA142808</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P30 CA043703</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P30 CA076292</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>T32 CA106493</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>06</Month><Day>08</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Oncotarget</MedlineTA><NlmUniqueID>101532965</NlmUniqueID><ISSNLinking>1949-2553</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">ALDEFLUOR</Keyword><Keyword MajorTopicYN="N">PI3K/Akt/mTOR signaling</Keyword><Keyword MajorTopicYN="N">apoptosis</Keyword><Keyword MajorTopicYN="N">colon cancer stem cells</Keyword><Keyword MajorTopicYN="N">tumorigenesis</Keyword></KeywordList><CoiStatement>CONFLICTS OF INTEREST The authors declare no conflicts of interest.</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year><Month>02</Month><Day>05</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2016</Year><Month>05</Month><Day>19</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>9</Month><Day>9</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2016</Year><Month>6</Month><Day>8</Day><Hour>0</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2016</Year><Month>6</Month><Day>8</Day><Hour>0</Hour><Minute>1</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">28881576</ArticleId><ArticleId IdType="doi">10.18632/oncotarget.9919</ArticleId><ArticleId IdType="pii">9919</ArticleId><ArticleId IdType="pmc">PMC5584153</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Nat Rev Clin Oncol. 2015 Oct;12(10):584-96</Citation><ArticleIdList><ArticleId IdType="pubmed">26122183</ArticleId></ArticleIdList></Reference><Reference><Citation>Cancer Res. 2009 Apr 15;69(8):3382-9</Citation><ArticleIdList><ArticleId IdType="pubmed">19336570</ArticleId></ArticleIdList></Reference><Reference><Citation>Mol Cancer. 2009 Jul 31;8:57</Citation><ArticleIdList><ArticleId IdType="pubmed">19646263</ArticleId></ArticleIdList></Reference><Reference><Citation>Biochem Biophys Res Commun. 2013 Feb 15;431(3):535-41</Citation><ArticleIdList><ArticleId 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Appelman</name><name sortKey="Baker, Henry V" sort="Baker, Henry V" uniqKey="Baker H" first="Henry V" last="Baker">Henry V. Baker</name><name sortKey="Barnholtz Sloan, Jill" sort="Barnholtz Sloan, Jill" uniqKey="Barnholtz Sloan J" first="Jill" last="Barnholtz-Sloan">Jill Barnholtz-Sloan</name><name sortKey="Berg, Annamarie" sort="Berg, Annamarie" uniqKey="Berg A" first="Annamarie" last="Berg">Annamarie Berg</name><name sortKey="Chen, Yi" sort="Chen, Yi" uniqKey="Chen Y" first="Yi" last="Chen">Yi Chen</name><name sortKey="Fisher, Robert C" sort="Fisher, Robert C" uniqKey="Fisher R" first="Robert C" last="Fisher">Robert C. Fisher</name><name sortKey="Fisher, Robert C" sort="Fisher, Robert C" uniqKey="Fisher R" first="Robert C" last="Fisher">Robert C. Fisher</name><name sortKey="Gittleman, Haley" sort="Gittleman, Haley" uniqKey="Gittleman H" first="Haley" last="Gittleman">Haley Gittleman</name><name sortKey="Huang, Emina H" sort="Huang, Emina H" uniqKey="Huang E" first="Emina H" last="Huang">Emina H. Huang</name><name sortKey="Huang, Emina H" sort="Huang, Emina H" uniqKey="Huang E" first="Emina H" last="Huang">Emina H. Huang</name><name sortKey="Koomen, John M" sort="Koomen, John M" uniqKey="Koomen J" first="John M" last="Koomen">John M. Koomen</name><name sortKey="Lopez, Maria Cecilia" sort="Lopez, Maria Cecilia" uniqKey="Lopez M" first="Maria-Cecilia" last="Lopez">Maria-Cecilia Lopez</name><name sortKey="Molina, L Alex" sort="Molina, L Alex" uniqKey="Molina L" first="L Alex" last="Molina">L Alex Molina</name><name sortKey="Shenoy, Anitha K" sort="Shenoy, Anitha K" uniqKey="Shenoy A" first="Anitha K" last="Shenoy">Anitha K. Shenoy</name><name sortKey="Signs, Steven" sort="Signs, Steven" uniqKey="Signs S" first="Steven" last="Signs">Steven Signs</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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