Inhibition of autophagy attenuates pancreatic cancer growth independent of TP53/TRP53 status.
Identifieur interne : 000288 ( PubMed/Curation ); précédent : 000287; suivant : 000289Inhibition of autophagy attenuates pancreatic cancer growth independent of TP53/TRP53 status.
Auteurs : Annan Yang [États-Unis] ; Alec C. Kimmelman [États-Unis]Source :
- Autophagy [ 1554-8635 ] ; 2014.
Descripteurs français
- KwdFr :
- Animaux, Autophagie (), Carcinome du canal pancréatique (anatomopathologie), Humains, Hydroxychloroquine (pharmacologie), Lignée cellulaire tumorale, Modèles animaux de maladie humaine, Protéine p53 suppresseur de tumeur (métabolisme), Souris, Tumeurs du pancréas (anatomopathologie), Tumeurs du pancréas (traitement médicamenteux).
- MESH :
- anatomopathologie : Carcinome du canal pancréatique, Tumeurs du pancréas.
- métabolisme : Protéine p53 suppresseur de tumeur.
- pharmacologie : Hydroxychloroquine.
- traitement médicamenteux : Tumeurs du pancréas.
- Animaux, Autophagie, Humains, Lignée cellulaire tumorale, Modèles animaux de maladie humaine, Souris.
English descriptors
- KwdEn :
- MESH :
- chemical , metabolism : Tumor Suppressor Protein p53.
- chemical , pharmacology : Hydroxychloroquine.
- drug effects : Autophagy.
- drug therapy : Pancreatic Neoplasms.
- pathology : Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms.
- Animals, Cell Line, Tumor, Disease Models, Animal, Humans, Mice.
Abstract
Basal levels of autophagy are elevated in most pancreatic ductal adenocarcinomas (PDAC). Suppressing autophagy pharmacologically using chloroquine (CQ) or genetically with RNAi to essential autophagy genes inhibits human pancreatic cancer growth in vitro and in vivo, which presents possible treatment opportunities for PDAC patients using the CQ-derivative hydroxychloroquine (HCQ). Indeed, such clinical trials are ongoing. However, autophagy is a complex cellular mechanism to maintain cell homeostasis under stress. Based on its biological role, a dual role of autophagy in tumorigenesis has been proposed: at tumor initiation, autophagy helps maintain genomic stability and prevent tumor initiation; while in advanced disease, autophagy degrades and recycles cellular components to meet the metabolic needs for rapid growth. This model was proven to be the case in mouse lung tumor models. However, in contrast to prior work in various PDAC model systems, loss of autophagy in PDAC mouse models with embryonic homozygous Trp53 deletion does not inhibit tumor growth and paradoxically increases progression. This raised concerns whether there may be a genotype-dependent reliance of PDAC on autophagy. In a recent study, our group used a Trp53 heterozygous mouse PDAC model and human PDX xenografts to address the question. Our results demonstrate that autophagy inhibition was effective against PDAC tumors irrespective of TP53/TRP53 status.
DOI: 10.4161/auto.29961
PubMed: 25046107
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Kimmelman</name><affiliation wicri:level="2"><nlm:affiliation>Division of Genomic Stability and DNA Repair; Department of Radiation Oncology; Dana Farber Cancer Institute; Boston, MA USA.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Division of Genomic Stability and DNA Repair; Department of Radiation Oncology; Dana Farber Cancer Institute; Boston</wicri:cityArea></affiliation></author></analytic><series><title level="j">Autophagy</title><idno type="eISSN">1554-8635</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Autophagy (drug effects)</term><term>Carcinoma, Pancreatic Ductal (pathology)</term><term>Cell Line, Tumor</term><term>Disease Models, Animal</term><term>Humans</term><term>Hydroxychloroquine (pharmacology)</term><term>Mice</term><term>Pancreatic Neoplasms (drug therapy)</term><term>Pancreatic Neoplasms (pathology)</term><term>Tumor Suppressor Protein p53 (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Autophagie ()</term><term>Carcinome du canal pancréatique (anatomopathologie)</term><term>Humains</term><term>Hydroxychloroquine (pharmacologie)</term><term>Lignée cellulaire tumorale</term><term>Modèles animaux de maladie humaine</term><term>Protéine p53 suppresseur de tumeur (métabolisme)</term><term>Souris</term><term>Tumeurs du pancréas (anatomopathologie)</term><term>Tumeurs du pancréas (traitement médicamenteux)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Tumor Suppressor Protein p53</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Hydroxychloroquine</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Carcinome du canal pancréatique</term><term>Tumeurs du pancréas</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Autophagy</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Pancreatic Neoplasms</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Protéine p53 suppresseur de tumeur</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Carcinoma, Pancreatic Ductal</term><term>Pancreatic Neoplasms</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Hydroxychloroquine</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Tumeurs du pancréas</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line, Tumor</term><term>Disease Models, Animal</term><term>Humans</term><term>Mice</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Autophagie</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Modèles animaux de maladie humaine</term><term>Souris</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Basal levels of autophagy are elevated in most pancreatic ductal adenocarcinomas (PDAC). Suppressing autophagy pharmacologically using chloroquine (CQ) or genetically with RNAi to essential autophagy genes inhibits human pancreatic cancer growth in vitro and in vivo, which presents possible treatment opportunities for PDAC patients using the CQ-derivative hydroxychloroquine (HCQ). Indeed, such clinical trials are ongoing. However, autophagy is a complex cellular mechanism to maintain cell homeostasis under stress. Based on its biological role, a dual role of autophagy in tumorigenesis has been proposed: at tumor initiation, autophagy helps maintain genomic stability and prevent tumor initiation; while in advanced disease, autophagy degrades and recycles cellular components to meet the metabolic needs for rapid growth. This model was proven to be the case in mouse lung tumor models. However, in contrast to prior work in various PDAC model systems, loss of autophagy in PDAC mouse models with embryonic homozygous Trp53 deletion does not inhibit tumor growth and paradoxically increases progression. This raised concerns whether there may be a genotype-dependent reliance of PDAC on autophagy. In a recent study, our group used a Trp53 heterozygous mouse PDAC model and human PDX xenografts to address the question. Our results demonstrate that autophagy inhibition was effective against PDAC tumors irrespective of TP53/TRP53 status. </div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">25046107</PMID><DateCompleted><Year>2015</Year><Month>07</Month><Day>21</Day></DateCompleted><DateRevised><Year>2016</Year><Month>10</Month><Day>19</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1554-8635</ISSN><JournalIssue CitedMedium="Internet"><Volume>10</Volume><Issue>9</Issue><PubDate><Year>2014</Year><Month>Sep</Month></PubDate></JournalIssue><Title>Autophagy</Title><ISOAbbreviation>Autophagy</ISOAbbreviation></Journal><ArticleTitle>Inhibition of autophagy attenuates pancreatic cancer growth independent of TP53/TRP53 status.</ArticleTitle><Pagination><MedlinePgn>1683-4</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.4161/auto.29961</ELocationID><Abstract><AbstractText>Basal levels of autophagy are elevated in most pancreatic ductal adenocarcinomas (PDAC). Suppressing autophagy pharmacologically using chloroquine (CQ) or genetically with RNAi to essential autophagy genes inhibits human pancreatic cancer growth in vitro and in vivo, which presents possible treatment opportunities for PDAC patients using the CQ-derivative hydroxychloroquine (HCQ). Indeed, such clinical trials are ongoing. However, autophagy is a complex cellular mechanism to maintain cell homeostasis under stress. Based on its biological role, a dual role of autophagy in tumorigenesis has been proposed: at tumor initiation, autophagy helps maintain genomic stability and prevent tumor initiation; while in advanced disease, autophagy degrades and recycles cellular components to meet the metabolic needs for rapid growth. This model was proven to be the case in mouse lung tumor models. However, in contrast to prior work in various PDAC model systems, loss of autophagy in PDAC mouse models with embryonic homozygous Trp53 deletion does not inhibit tumor growth and paradoxically increases progression. This raised concerns whether there may be a genotype-dependent reliance of PDAC on autophagy. In a recent study, our group used a Trp53 heterozygous mouse PDAC model and human PDX xenografts to address the question. Our results demonstrate that autophagy inhibition was effective against PDAC tumors irrespective of TP53/TRP53 status. </AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Yang</LastName><ForeName>Annan</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Division of Genomic Stability and DNA Repair; Department of Radiation Oncology; Dana Farber Cancer Institute; Boston, MA USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kimmelman</LastName><ForeName>Alec C</ForeName><Initials>AC</Initials><AffiliationInfo><Affiliation>Division of Genomic Stability and DNA Repair; Department of Radiation Oncology; Dana Farber Cancer Institute; Boston, MA USA.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 CA157490</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01CA157490</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2014</Year><Month>07</Month><Day>17</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Autophagy</MedlineTA><NlmUniqueID>101265188</NlmUniqueID><ISSNLinking>1554-8627</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D016159">Tumor Suppressor Protein p53</NameOfSubstance></Chemical><Chemical><RegistryNumber>4QWG6N8QKH</RegistryNumber><NameOfSubstance UI="D006886">Hydroxychloroquine</NameOfSubstance></Chemical></ChemicalList><SupplMeshList><SupplMeshName Type="Disease" UI="C562463">Pancreatic Carcinoma</SupplMeshName></SupplMeshList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001343" MajorTopicYN="N">Autophagy</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D021441" MajorTopicYN="N">Carcinoma, Pancreatic Ductal</DescriptorName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004195" MajorTopicYN="N">Disease Models, Animal</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006886" MajorTopicYN="N">Hydroxychloroquine</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010190" MajorTopicYN="N">Pancreatic Neoplasms</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016159" MajorTopicYN="N">Tumor Suppressor Protein p53</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Atg5</Keyword><Keyword MajorTopicYN="N">PDAC</Keyword><Keyword MajorTopicYN="N">TP53</Keyword><Keyword MajorTopicYN="N">Trp53</Keyword><Keyword MajorTopicYN="N">autophagy</Keyword><Keyword MajorTopicYN="N">chloroquine</Keyword><Keyword MajorTopicYN="N">pancreatic cancer</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2014</Year><Month>7</Month><Day>22</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2014</Year><Month>7</Month><Day>22</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2015</Year><Month>7</Month><Day>22</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">25046107</ArticleId><ArticleId IdType="pii">29961</ArticleId><ArticleId IdType="doi">10.4161/auto.29961</ArticleId><ArticleId IdType="pmc">PMC4206544</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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