Regulation of autophagy and chloroquine sensitivity by oncogenic RAS in vitro is context-dependent.
Identifieur interne : 001009 ( Main/Exploration ); précédent : 001008; suivant : 001010Regulation of autophagy and chloroquine sensitivity by oncogenic RAS in vitro is context-dependent.
Auteurs : Michael J. Morgan [États-Unis] ; Graciela Gamez [États-Unis] ; Christina Menke [États-Unis] ; Ariel Hernandez [États-Unis] ; Jacqueline Thorburn [États-Unis] ; Freddi Gidan [États-Unis] ; Leah Staskiewicz [États-Unis] ; Shellie Morgan [États-Unis] ; Christopher Cummings [États-Unis] ; Paola Maycotte [États-Unis] ; Andrew Thorburn [États-Unis]Source :
- Autophagy [ 1554-8635 ] ; 2014.
Descripteurs français
- KwdFr :
- MESH :
- anatomopathologie : Tumeurs du poumon.
- métabolisme : Phagosomes, Protéine p53 suppresseur de tumeur, Protéines G ras.
- pharmacologie : Chloroquine.
- Autophagie, Cellules HEK293, Humains, Lignée cellulaire tumorale, Oncogènes, Phagosomes, Prolifération cellulaire.
English descriptors
- KwdEn :
- MESH :
- chemical , metabolism : Tumor Suppressor Protein p53, ras Proteins.
- chemical , pharmacology : Chloroquine.
- drug effects : Autophagy, Cell Proliferation, Phagosomes.
- metabolism : Phagosomes.
- pathology : Lung Neoplasms.
- Cell Line, Tumor, HEK293 Cells, Humans, Oncogenes.
Abstract
Chloroquine (CQ) is an antimalarial drug and late-stage inhibitor of autophagy currently FDA-approved for use in the treatment of rheumatoid arthritis and other autoimmune diseases. Based primarily on its ability to inhibit autophagy, CQ and its derivative, hydroxychloroquine, are currently being investigated as primary or adjuvant therapy in multiple clinical trials for cancer treatment. Oncogenic RAS has previously been shown to regulate autophagic flux, and cancers with high incidence of RAS mutations, such as pancreatic cancer, have been described in the literature as being particularly susceptible to CQ treatment, leading to the hypothesis that oncogenic RAS makes cancer cells dependent on autophagy. This autophagy "addiction" suggests that the mutation status of RAS in tumors could identify patients who would be more likely to benefit from CQ therapy. Here we show that RAS mutation status itself is unlikely to be beneficial in such a patient selection because oncogenic RAS does not always promote autophagy addiction. Moreover, oncogenic RAS can have opposite effects on both autophagic flux and CQ sensitivity in different cells. Finally, for any given cell type, the positive or negative effect of oncogenic RAS on autophagy does not necessarily predict whether RAS will promote or inhibit CQ-mediated toxicity. Thus, although our results confirm that different tumor cell lines display marked differences in how they respond to autophagy inhibition, these differences can occur irrespective of RAS mutation status and, in different contexts, can either promote or reduce chloroquine sensitivity of tumor cells.
DOI: 10.4161/auto.32135
PubMed: 25136801
Affiliations:
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Morgan</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA; University of Colorado Comprehensive Cancer Center; Aurora, CO USA.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Colorado</region></placeName><wicri:cityArea>Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA; University of Colorado Comprehensive Cancer Center; Aurora</wicri:cityArea></affiliation></author><author><name sortKey="Gamez, Graciela" sort="Gamez, Graciela" uniqKey="Gamez G" first="Graciela" last="Gamez">Graciela Gamez</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Colorado</region></placeName><wicri:cityArea>Department of Pharmacology; University of Colorado School of Medicine; Aurora</wicri:cityArea></affiliation></author><author><name sortKey="Menke, Christina" sort="Menke, Christina" uniqKey="Menke C" first="Christina" last="Menke">Christina Menke</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Colorado</region></placeName><wicri:cityArea>Department of Pharmacology; University of Colorado School of Medicine; Aurora</wicri:cityArea></affiliation></author><author><name sortKey="Hernandez, Ariel" sort="Hernandez, Ariel" uniqKey="Hernandez A" first="Ariel" last="Hernandez">Ariel Hernandez</name><affiliation wicri:level="2"><nlm:affiliation>University of Colorado School of Medicine; Medical Scientist Training Program; Aurora, CO USA.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Colorado</region></placeName><wicri:cityArea>University of Colorado School of Medicine; Medical Scientist Training Program; Aurora</wicri:cityArea></affiliation></author><author><name sortKey="Thorburn, Jacqueline" sort="Thorburn, Jacqueline" uniqKey="Thorburn J" first="Jacqueline" last="Thorburn">Jacqueline Thorburn</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Colorado</region></placeName><wicri:cityArea>Department of Pharmacology; University of Colorado School of Medicine; Aurora</wicri:cityArea></affiliation></author><author><name sortKey="Gidan, Freddi" sort="Gidan, Freddi" uniqKey="Gidan F" first="Freddi" last="Gidan">Freddi Gidan</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Colorado</region></placeName><wicri:cityArea>Department of Pharmacology; University of Colorado School of Medicine; Aurora</wicri:cityArea></affiliation></author><author><name sortKey="Staskiewicz, Leah" sort="Staskiewicz, Leah" uniqKey="Staskiewicz L" first="Leah" last="Staskiewicz">Leah Staskiewicz</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Colorado</region></placeName><wicri:cityArea>Department of Pharmacology; University of Colorado School of Medicine; Aurora</wicri:cityArea></affiliation></author><author><name sortKey="Morgan, Shellie" sort="Morgan, Shellie" uniqKey="Morgan S" first="Shellie" last="Morgan">Shellie Morgan</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Colorado</region></placeName><wicri:cityArea>Department of Pharmacology; University of Colorado School of Medicine; Aurora</wicri:cityArea></affiliation></author><author><name sortKey="Cummings, Christopher" sort="Cummings, Christopher" uniqKey="Cummings C" first="Christopher" last="Cummings">Christopher Cummings</name><affiliation wicri:level="2"><nlm:affiliation>University of Colorado School of Medicine; Medical Scientist Training Program; Aurora, CO USA.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Colorado</region></placeName><wicri:cityArea>University of Colorado School of Medicine; Medical Scientist Training Program; Aurora</wicri:cityArea></affiliation></author><author><name sortKey="Maycotte, Paola" sort="Maycotte, Paola" uniqKey="Maycotte P" first="Paola" last="Maycotte">Paola Maycotte</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Colorado</region></placeName><wicri:cityArea>Department of Pharmacology; University of Colorado School of Medicine; Aurora</wicri:cityArea></affiliation></author><author><name sortKey="Thorburn, Andrew" sort="Thorburn, Andrew" uniqKey="Thorburn A" first="Andrew" last="Thorburn">Andrew Thorburn</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA; University of Colorado Comprehensive Cancer Center; Aurora, CO USA.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Colorado</region></placeName><wicri:cityArea>Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA; University of Colorado Comprehensive Cancer Center; Aurora</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>Autophagy (drug effects)</term><term>Cell Line, Tumor</term><term>Cell Proliferation (drug effects)</term><term>Chloroquine (pharmacology)</term><term>HEK293 Cells</term><term>Humans</term><term>Lung Neoplasms (pathology)</term><term>Oncogenes</term><term>Phagosomes (drug effects)</term><term>Phagosomes (metabolism)</term><term>Tumor Suppressor Protein p53 (metabolism)</term><term>ras Proteins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Autophagie ()</term><term>Cellules HEK293</term><term>Chloroquine (pharmacologie)</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Oncogènes</term><term>Phagosomes ()</term><term>Phagosomes (métabolisme)</term><term>Prolifération cellulaire ()</term><term>Protéine p53 suppresseur de tumeur (métabolisme)</term><term>Protéines G ras (métabolisme)</term><term>Tumeurs du poumon (anatomopathologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Tumor Suppressor Protein p53</term><term>ras Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Chloroquine</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Autophagy</term><term>Cell Proliferation</term><term>Phagosomes</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Phagosomes</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Phagosomes</term><term>Protéine p53 suppresseur de tumeur</term><term>Protéines G ras</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Chloroquine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term><term>HEK293 Cells</term><term>Humans</term><term>Oncogenes</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Autophagie</term><term>Cellules HEK293</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Oncogènes</term><term>Phagosomes</term><term>Prolifération cellulaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Chloroquine (CQ) is an antimalarial drug and late-stage inhibitor of autophagy currently FDA-approved for use in the treatment of rheumatoid arthritis and other autoimmune diseases. Based primarily on its ability to inhibit autophagy, CQ and its derivative, hydroxychloroquine, are currently being investigated as primary or adjuvant therapy in multiple clinical trials for cancer treatment. Oncogenic RAS has previously been shown to regulate autophagic flux, and cancers with high incidence of RAS mutations, such as pancreatic cancer, have been described in the literature as being particularly susceptible to CQ treatment, leading to the hypothesis that oncogenic RAS makes cancer cells dependent on autophagy. This autophagy "addiction" suggests that the mutation status of RAS in tumors could identify patients who would be more likely to benefit from CQ therapy. Here we show that RAS mutation status itself is unlikely to be beneficial in such a patient selection because oncogenic RAS does not always promote autophagy addiction. Moreover, oncogenic RAS can have opposite effects on both autophagic flux and CQ sensitivity in different cells. Finally, for any given cell type, the positive or negative effect of oncogenic RAS on autophagy does not necessarily predict whether RAS will promote or inhibit CQ-mediated toxicity. Thus, although our results confirm that different tumor cell lines display marked differences in how they respond to autophagy inhibition, these differences can occur irrespective of RAS mutation status and, in different contexts, can either promote or reduce chloroquine sensitivity of tumor cells. </div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Colorado</li></region></list><tree><country name="États-Unis"><region name="Colorado"><name sortKey="Morgan, Michael J" sort="Morgan, Michael J" uniqKey="Morgan M" first="Michael J" last="Morgan">Michael J. Morgan</name></region><name sortKey="Cummings, Christopher" sort="Cummings, Christopher" uniqKey="Cummings C" first="Christopher" last="Cummings">Christopher Cummings</name><name sortKey="Gamez, Graciela" sort="Gamez, Graciela" uniqKey="Gamez G" first="Graciela" last="Gamez">Graciela Gamez</name><name sortKey="Gidan, Freddi" sort="Gidan, Freddi" uniqKey="Gidan F" first="Freddi" last="Gidan">Freddi Gidan</name><name sortKey="Hernandez, Ariel" sort="Hernandez, Ariel" uniqKey="Hernandez A" first="Ariel" last="Hernandez">Ariel Hernandez</name><name sortKey="Maycotte, Paola" sort="Maycotte, Paola" uniqKey="Maycotte P" first="Paola" last="Maycotte">Paola Maycotte</name><name sortKey="Menke, Christina" sort="Menke, Christina" uniqKey="Menke C" first="Christina" last="Menke">Christina Menke</name><name sortKey="Morgan, Shellie" sort="Morgan, Shellie" uniqKey="Morgan S" first="Shellie" last="Morgan">Shellie Morgan</name><name sortKey="Staskiewicz, Leah" sort="Staskiewicz, Leah" uniqKey="Staskiewicz L" first="Leah" last="Staskiewicz">Leah Staskiewicz</name><name sortKey="Thorburn, Andrew" sort="Thorburn, Andrew" uniqKey="Thorburn A" first="Andrew" last="Thorburn">Andrew Thorburn</name><name sortKey="Thorburn, Jacqueline" sort="Thorburn, Jacqueline" uniqKey="Thorburn J" first="Jacqueline" last="Thorburn">Jacqueline Thorburn</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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