Oxidative pentose phosphate pathway inhibition is a key determinant of antimalarial induced cancer cell death.
Identifieur interne : 000D62 ( Main/Exploration ); précédent : 000D61; suivant : 000D63Oxidative pentose phosphate pathway inhibition is a key determinant of antimalarial induced cancer cell death.
Auteurs : E. Salas [États-Unis] ; S. Roy [États-Unis] ; T. Marsh [États-Unis] ; B. Rubin [États-Unis] ; J. Debnath [États-Unis]Source :
- Oncogene [ 1476-5594 ] ; 2016.
Descripteurs français
- KwdFr :
- Antipaludiques (pharmacologie), Apoptose (), Autophagie (), Carcinome pulmonaire non à petites cellules (anatomopathologie), Chloroquine (pharmacologie), Humains, Lignée cellulaire tumorale, Mutation, Oxydoréduction (), Prolifération cellulaire (), Protéine p53 suppresseur de tumeur (métabolisme), Protéines proto-oncogènes p21(ras) (génétique), Tumeurs du poumon (anatomopathologie), Voie des pentoses phosphates ().
- MESH :
- anatomopathologie : Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- génétique : Protéines proto-oncogènes p21(ras).
- métabolisme : Protéine p53 suppresseur de tumeur.
- pharmacologie : Antipaludiques, Chloroquine.
- Apoptose, Autophagie, Humains, Lignée cellulaire tumorale, Mutation, Oxydoréduction, Prolifération cellulaire, Voie des pentoses phosphates.
English descriptors
- KwdEn :
- Antimalarials (pharmacology), Apoptosis (drug effects), Autophagy (drug effects), Carcinoma, Non-Small-Cell Lung (pathology), Cell Line, Tumor, Cell Proliferation (drug effects), Chloroquine (pharmacology), Humans, Lung Neoplasms (pathology), Mutation, Oxidation-Reduction (drug effects), Pentose Phosphate Pathway (drug effects), Proto-Oncogene Proteins p21(ras) (genetics), Tumor Suppressor Protein p53 (metabolism).
- MESH :
- chemical , genetics : Proto-Oncogene Proteins p21(ras).
- chemical , metabolism : Tumor Suppressor Protein p53.
- chemical , pharmacology : Antimalarials, Chloroquine.
- drug effects : Apoptosis, Autophagy, Cell Proliferation, Oxidation-Reduction, Pentose Phosphate Pathway.
- pathology : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- Cell Line, Tumor, Humans, Mutation.
Abstract
Despite immense interest in using antimalarials as autophagy inhibitors to treat cancer, it remains unclear whether these agents act predominantly via autophagy inhibition or whether other pathways direct their anti-cancer properties. By comparing the treatment effects of the antimalarials chloroquine (CQ) and quinacrine (Q) on KRAS mutant lung cancer cells, we demonstrate that inhibition of the oxidative arm of the pentose phosphate pathway (oxPPP) is required for antimalarial induced apoptosis. Despite inhibiting autophagy, neither CQ treatment nor RNAi against autophagy regulators (ATGs) promote cell death. In contrast, Q triggers high levels of apoptosis, both in vitro and in vivo, and this phenotype requires both autophagy inhibition and p53-dependent inhibition of the oxPPP. Simultaneous genetic targeting of the oxPPP and autophagy is sufficient to trigger apoptosis in lung cancer cells, including cells lacking p53. Thus, in addition to reduced autophagy, oxPPP inhibition serves as an important determinant of antimalarial cytotoxicity in cancer cells.
DOI: 10.1038/onc.2015.348
PubMed: 26434592
Affiliations:
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Salas</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Roy, S" sort="Roy, S" uniqKey="Roy S" first="S" last="Roy">S. Roy</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Marsh, T" sort="Marsh, T" uniqKey="Marsh T" first="T" last="Marsh">T. Marsh</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Rubin, B" sort="Rubin, B" uniqKey="Rubin B" first="B" last="Rubin">B. 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Debnath</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author></analytic><series><title level="j">Oncogene</title><idno type="eISSN">1476-5594</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antimalarials (pharmacology)</term><term>Apoptosis (drug effects)</term><term>Autophagy (drug effects)</term><term>Carcinoma, Non-Small-Cell Lung (pathology)</term><term>Cell Line, Tumor</term><term>Cell Proliferation (drug effects)</term><term>Chloroquine (pharmacology)</term><term>Humans</term><term>Lung Neoplasms (pathology)</term><term>Mutation</term><term>Oxidation-Reduction (drug effects)</term><term>Pentose Phosphate Pathway (drug effects)</term><term>Proto-Oncogene Proteins p21(ras) (genetics)</term><term>Tumor Suppressor Protein p53 (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Antipaludiques (pharmacologie)</term><term>Apoptose ()</term><term>Autophagie ()</term><term>Carcinome pulmonaire non à petites cellules (anatomopathologie)</term><term>Chloroquine (pharmacologie)</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Mutation</term><term>Oxydoréduction ()</term><term>Prolifération cellulaire ()</term><term>Protéine p53 suppresseur de tumeur (métabolisme)</term><term>Protéines proto-oncogènes p21(ras) (génétique)</term><term>Tumeurs du poumon (anatomopathologie)</term><term>Voie des pentoses phosphates ()</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Proto-Oncogene Proteins p21(ras)</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>Antimalarials</term><term>Chloroquine</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Carcinome pulmonaire non à petites cellules</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term><term>Autophagy</term><term>Cell Proliferation</term><term>Oxidation-Reduction</term><term>Pentose Phosphate Pathway</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Protéines proto-oncogènes p21(ras)</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, Non-Small-Cell Lung</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antipaludiques</term><term>Chloroquine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term><term>Humans</term><term>Mutation</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Apoptose</term><term>Autophagie</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Mutation</term><term>Oxydoréduction</term><term>Prolifération cellulaire</term><term>Voie des pentoses phosphates</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Despite immense interest in using antimalarials as autophagy inhibitors to treat cancer, it remains unclear whether these agents act predominantly via autophagy inhibition or whether other pathways direct their anti-cancer properties. By comparing the treatment effects of the antimalarials chloroquine (CQ) and quinacrine (Q) on KRAS mutant lung cancer cells, we demonstrate that inhibition of the oxidative arm of the pentose phosphate pathway (oxPPP) is required for antimalarial induced apoptosis. Despite inhibiting autophagy, neither CQ treatment nor RNAi against autophagy regulators (ATGs) promote cell death. In contrast, Q triggers high levels of apoptosis, both in vitro and in vivo, and this phenotype requires both autophagy inhibition and p53-dependent inhibition of the oxPPP. Simultaneous genetic targeting of the oxPPP and autophagy is sufficient to trigger apoptosis in lung cancer cells, including cells lacking p53. Thus, in addition to reduced autophagy, oxPPP inhibition serves as an important determinant of antimalarial cytotoxicity in cancer cells.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Californie</li><li>Ohio</li></region></list><tree><country name="États-Unis"><region name="Californie"><name sortKey="Salas, E" sort="Salas, E" uniqKey="Salas E" first="E" last="Salas">E. Salas</name></region><name sortKey="Debnath, J" sort="Debnath, J" uniqKey="Debnath J" first="J" last="Debnath">J. Debnath</name><name sortKey="Marsh, T" sort="Marsh, T" uniqKey="Marsh T" first="T" last="Marsh">T. Marsh</name><name sortKey="Roy, S" sort="Roy, S" uniqKey="Roy S" first="S" last="Roy">S. Roy</name><name sortKey="Rubin, B" sort="Rubin, B" uniqKey="Rubin B" first="B" last="Rubin">B. Rubin</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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