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TRPM2 channel-mediated regulation of autophagy maintains mitochondrial function and promotes gastric cancer cell survival via the JNK-signaling pathway.

Identifieur interne : 000476 ( Main/Exploration ); précédent : 000475; suivant : 000477

TRPM2 channel-mediated regulation of autophagy maintains mitochondrial function and promotes gastric cancer cell survival via the JNK-signaling pathway.

Auteurs : Shekoufeh Almasi ; Barry E. Kennedy ; Mariam El-Aghil ; Andra M. Sterea ; Shashi Gujar [Canada] ; Santiago Partida-Sánchez [États-Unis] ; Yassine El Hiani [Canada]

Source :

RBID : pubmed:29343514

Descripteurs français

English descriptors

Abstract

A lack of effective treatment is one of the main factors contributing to gastric cancer-related death. Discovering effective targets and understanding their underlying anti-cancer mechanism are key to achieving the best response to treatment and to limiting side effects. Although recent studies have shown that the cation channel transient receptor potential melastatin-2 (TRPM2) is crucial for cancer cell survival, the exact mechanism remains unclear, limiting its therapeutic potential. Here, using molecular and functional assays, we investigated the role of TRPM2 in survival of gastric cancer cells. Our results indicated that TRPM2 knockdown in AGS and MKN-45 cells decreases cell proliferation and enhances apoptosis. We also observed that the TRPM2 knockdown impairs mitochondrial metabolism, indicated by a decrease in basal and maximal mitochondrial oxygen consumption rates and ATP production. These mitochondrial defects coincided with a decrease in autophagy and mitophagy, indicated by reduced levels of autophagy- and mitophagy-associated proteins (i.e. ATGs, LC3A/B II, and BNIP3). Moreover, we found that TRPM2 modulates autophagy through a c-Jun N-terminal kinase (JNK)-dependent and mechanistic target of rapamycin-independent pathway. We conclude that in the absence of TRPM2, down-regulation of the JNK-signaling pathway impairs autophagy, ultimately causing the accumulation of damaged mitochondria and death of gastric cancer cells. Of note, by inhibiting cell proliferation and promoting apoptosis, the TRPM2 down-regulation enhanced the efficacy of paclitaxel and doxorubicin in gastric cancer cells. Collectively, we provide compelling evidence that TRPM2 inhibition may benefit therapeutic approaches for managing gastric cancer.

DOI: 10.1074/jbc.M117.817635
PubMed: 29343514
PubMed Central: PMC5846146


Affiliations:


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Le document en format XML

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<term>Adenocarcinoma (drug therapy)</term>
<term>Adenocarcinoma (metabolism)</term>
<term>Adenocarcinoma (mortality)</term>
<term>Adenocarcinoma (pathology)</term>
<term>Antibiotics, Antineoplastic (pharmacology)</term>
<term>Antineoplastic Agents, Phytogenic (pharmacology)</term>
<term>Apoptosis (drug effects)</term>
<term>Autophagy (MeSH)</term>
<term>Cell Line, Tumor (MeSH)</term>
<term>Cell Proliferation (drug effects)</term>
<term>Cell Survival (drug effects)</term>
<term>Doxorubicin (pharmacology)</term>
<term>Electronic Health Records (MeSH)</term>
<term>Gene Expression Regulation, Neoplastic (drug effects)</term>
<term>Humans (MeSH)</term>
<term>MAP Kinase Signaling System (drug effects)</term>
<term>Mitochondria (drug effects)</term>
<term>Mitochondria (enzymology)</term>
<term>Mitochondria (metabolism)</term>
<term>Mitophagy (drug effects)</term>
<term>Neoplasm Proteins (antagonists & inhibitors)</term>
<term>Neoplasm Proteins (genetics)</term>
<term>Neoplasm Proteins (metabolism)</term>
<term>Oxidative Phosphorylation (drug effects)</term>
<term>Paclitaxel (pharmacology)</term>
<term>RNA Interference (MeSH)</term>
<term>Stomach Neoplasms (drug therapy)</term>
<term>Stomach Neoplasms (metabolism)</term>
<term>Stomach Neoplasms (mortality)</term>
<term>Stomach Neoplasms (pathology)</term>
<term>Survival Analysis (MeSH)</term>
<term>TRPM Cation Channels (antagonists & inhibitors)</term>
<term>TRPM Cation Channels (genetics)</term>
<term>TRPM Cation Channels (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr">
<term>Adénocarcinome (anatomopathologie)</term>
<term>Adénocarcinome (mortalité)</term>
<term>Adénocarcinome (métabolisme)</term>
<term>Adénocarcinome (traitement médicamenteux)</term>
<term>Analyse de survie (MeSH)</term>
<term>Antibiotiques antinéoplasiques (pharmacologie)</term>
<term>Antinéoplasiques d'origine végétale (pharmacologie)</term>
<term>Apoptose (effets des médicaments et des substances chimiques)</term>
<term>Autophagie (MeSH)</term>
<term>Canaux cationiques TRPM (antagonistes et inhibiteurs)</term>
<term>Canaux cationiques TRPM (génétique)</term>
<term>Canaux cationiques TRPM (métabolisme)</term>
<term>Dossiers médicaux électroniques (MeSH)</term>
<term>Doxorubicine (pharmacologie)</term>
<term>Humains (MeSH)</term>
<term>Interférence par ARN (MeSH)</term>
<term>Lignée cellulaire tumorale (MeSH)</term>
<term>Mitochondries (effets des médicaments et des substances chimiques)</term>
<term>Mitochondries (enzymologie)</term>
<term>Mitochondries (métabolisme)</term>
<term>Paclitaxel (pharmacologie)</term>
<term>Phosphorylation oxydative (effets des médicaments et des substances chimiques)</term>
<term>Prolifération cellulaire (effets des médicaments et des substances chimiques)</term>
<term>Protéines tumorales (antagonistes et inhibiteurs)</term>
<term>Protéines tumorales (génétique)</term>
<term>Protéines tumorales (métabolisme)</term>
<term>Régulation de l'expression des gènes tumoraux (effets des médicaments et des substances chimiques)</term>
<term>Survie cellulaire (effets des médicaments et des substances chimiques)</term>
<term>Système de signalisation des MAP kinases (effets des médicaments et des substances chimiques)</term>
<term>Tumeurs de l'estomac (anatomopathologie)</term>
<term>Tumeurs de l'estomac (mortalité)</term>
<term>Tumeurs de l'estomac (métabolisme)</term>
<term>Tumeurs de l'estomac (traitement médicamenteux)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en">
<term>Neoplasm Proteins</term>
<term>TRPM Cation Channels</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en">
<term>Neoplasm Proteins</term>
<term>TRPM Cation Channels</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en">
<term>Neoplasm Proteins</term>
<term>TRPM Cation Channels</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en">
<term>Antibiotics, Antineoplastic</term>
<term>Antineoplastic Agents, Phytogenic</term>
<term>Doxorubicin</term>
<term>Paclitaxel</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr">
<term>Adénocarcinome</term>
<term>Tumeurs de l'estomac</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr">
<term>Canaux cationiques TRPM</term>
<term>Protéines tumorales</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en">
<term>Apoptosis</term>
<term>Cell Proliferation</term>
<term>Cell Survival</term>
<term>Gene Expression Regulation, Neoplastic</term>
<term>MAP Kinase Signaling System</term>
<term>Mitochondria</term>
<term>Mitophagy</term>
<term>Oxidative Phosphorylation</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en">
<term>Adenocarcinoma</term>
<term>Stomach Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr">
<term>Apoptose</term>
<term>Mitochondries</term>
<term>Phosphorylation oxydative</term>
<term>Prolifération cellulaire</term>
<term>Régulation de l'expression des gènes tumoraux</term>
<term>Survie cellulaire</term>
<term>Système de signalisation des MAP kinases</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr">
<term>Mitochondries</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en">
<term>Mitochondria</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr">
<term>Canaux cationiques TRPM</term>
<term>Protéines tumorales</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en">
<term>Adenocarcinoma</term>
<term>Mitochondria</term>
<term>Stomach Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="mortality" xml:lang="en">
<term>Adenocarcinoma</term>
<term>Stomach Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="mortalité" xml:lang="fr">
<term>Adénocarcinome</term>
<term>Tumeurs de l'estomac</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Adénocarcinome</term>
<term>Canaux cationiques TRPM</term>
<term>Mitochondries</term>
<term>Protéines tumorales</term>
<term>Tumeurs de l'estomac</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en">
<term>Adenocarcinoma</term>
<term>Stomach Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr">
<term>Antibiotiques antinéoplasiques</term>
<term>Antinéoplasiques d'origine végétale</term>
<term>Doxorubicine</term>
<term>Paclitaxel</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr">
<term>Adénocarcinome</term>
<term>Tumeurs de l'estomac</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Autophagy</term>
<term>Cell Line, Tumor</term>
<term>Electronic Health Records</term>
<term>Humans</term>
<term>RNA Interference</term>
<term>Survival Analysis</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr">
<term>Analyse de survie</term>
<term>Autophagie</term>
<term>Dossiers médicaux électroniques</term>
<term>Humains</term>
<term>Interférence par ARN</term>
<term>Lignée cellulaire tumorale</term>
</keywords>
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<front>
<div type="abstract" xml:lang="en">A lack of effective treatment is one of the main factors contributing to gastric cancer-related death. Discovering effective targets and understanding their underlying anti-cancer mechanism are key to achieving the best response to treatment and to limiting side effects. Although recent studies have shown that the cation channel transient receptor potential melastatin-2 (TRPM2) is crucial for cancer cell survival, the exact mechanism remains unclear, limiting its therapeutic potential. Here, using molecular and functional assays, we investigated the role of TRPM2 in survival of gastric cancer cells. Our results indicated that TRPM2 knockdown in AGS and MKN-45 cells decreases cell proliferation and enhances apoptosis. We also observed that the TRPM2 knockdown impairs mitochondrial metabolism, indicated by a decrease in basal and maximal mitochondrial oxygen consumption rates and ATP production. These mitochondrial defects coincided with a decrease in autophagy and mitophagy, indicated by reduced levels of autophagy- and mitophagy-associated proteins (
<i>i.e.</i>
ATGs, LC3A/B II, and BNIP3). Moreover, we found that TRPM2 modulates autophagy through a c-Jun N-terminal kinase (JNK)-dependent and mechanistic target of rapamycin-independent pathway. We conclude that in the absence of TRPM2, down-regulation of the JNK-signaling pathway impairs autophagy, ultimately causing the accumulation of damaged mitochondria and death of gastric cancer cells. Of note, by inhibiting cell proliferation and promoting apoptosis, the TRPM2 down-regulation enhanced the efficacy of paclitaxel and doxorubicin in gastric cancer cells. Collectively, we provide compelling evidence that TRPM2 inhibition may benefit therapeutic approaches for managing gastric cancer.</div>
</front>
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<Year>2019</Year>
<Month>01</Month>
<Day>07</Day>
</DateCompleted>
<DateRevised>
<Year>2019</Year>
<Month>12</Month>
<Day>10</Day>
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<ISSN IssnType="Electronic">1083-351X</ISSN>
<JournalIssue CitedMedium="Internet">
<Volume>293</Volume>
<Issue>10</Issue>
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<Year>2018</Year>
<Month>03</Month>
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<Title>The Journal of biological chemistry</Title>
<ISOAbbreviation>J Biol Chem</ISOAbbreviation>
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<ArticleTitle>TRPM2 channel-mediated regulation of autophagy maintains mitochondrial function and promotes gastric cancer cell survival via the JNK-signaling pathway.</ArticleTitle>
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<MedlinePgn>3637-3650</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1074/jbc.M117.817635</ELocationID>
<Abstract>
<AbstractText>A lack of effective treatment is one of the main factors contributing to gastric cancer-related death. Discovering effective targets and understanding their underlying anti-cancer mechanism are key to achieving the best response to treatment and to limiting side effects. Although recent studies have shown that the cation channel transient receptor potential melastatin-2 (TRPM2) is crucial for cancer cell survival, the exact mechanism remains unclear, limiting its therapeutic potential. Here, using molecular and functional assays, we investigated the role of TRPM2 in survival of gastric cancer cells. Our results indicated that TRPM2 knockdown in AGS and MKN-45 cells decreases cell proliferation and enhances apoptosis. We also observed that the TRPM2 knockdown impairs mitochondrial metabolism, indicated by a decrease in basal and maximal mitochondrial oxygen consumption rates and ATP production. These mitochondrial defects coincided with a decrease in autophagy and mitophagy, indicated by reduced levels of autophagy- and mitophagy-associated proteins (
<i>i.e.</i>
ATGs, LC3A/B II, and BNIP3). Moreover, we found that TRPM2 modulates autophagy through a c-Jun N-terminal kinase (JNK)-dependent and mechanistic target of rapamycin-independent pathway. We conclude that in the absence of TRPM2, down-regulation of the JNK-signaling pathway impairs autophagy, ultimately causing the accumulation of damaged mitochondria and death of gastric cancer cells. Of note, by inhibiting cell proliferation and promoting apoptosis, the TRPM2 down-regulation enhanced the efficacy of paclitaxel and doxorubicin in gastric cancer cells. Collectively, we provide compelling evidence that TRPM2 inhibition may benefit therapeutic approaches for managing gastric cancer.</AbstractText>
<CopyrightInformation>© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.</CopyrightInformation>
</Abstract>
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<LastName>Kennedy</LastName>
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<LastName>Sterea</LastName>
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<AffiliationInfo>
<Affiliation>Microbiology and Immunology, and.</Affiliation>
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<ForeName>Santiago</ForeName>
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