The checkpoint 1 kinase inhibitor LY2603618 induces cell cycle arrest, DNA damage response and autophagy in cancer cells.
Identifieur interne : 001003 ( Main/Exploration ); précédent : 001002; suivant : 001004The checkpoint 1 kinase inhibitor LY2603618 induces cell cycle arrest, DNA damage response and autophagy in cancer cells.
Auteurs : Feng-Ze Wang [République populaire de Chine] ; Hong-Rong Fei ; Ying-Jie Cui ; Ying-Kun Sun ; Zhao-Mei Li ; Xue-Ying Wang ; Xiao-Yi Yang ; Ji-Guo Zhang ; Bao-Liang SunSource :
- Apoptosis : an international journal on programmed cell death [ 1573-675X ] ; 2014.
Descripteurs français
- KwdFr :
- Altération de l'ADN, Antinéoplasiques (pharmacologie), Antirhumatismaux (pharmacologie), Autophagie (), Carcinome pulmonaire non à petites cellules, Caspases (métabolisme), Checkpoint kinase 1, Chloroquine (pharmacologie), Humains, Inhibiteurs de protéines kinases (pharmacologie), Lignée cellulaire tumorale (), MAP Kinase Kinase 4 (métabolisme), Phosphorylation (), Phénylurées (pharmacologie), Points de contrôle de la phase G2 du cycle cellulaire, Prolifération cellulaire (), Protein kinases (métabolisme), Protéines nucléaires (métabolisme), Pyrazines (pharmacologie), Réparation de l'ADN (), Survie cellulaire (), Sérine (métabolisme), Tumeurs du poumon, p38 Mitogen-Activated Protein Kinases (métabolisme).
- MESH :
- métabolisme : Caspases, MAP Kinase Kinase 4, Protein kinases, Protéines nucléaires, Sérine, p38 Mitogen-Activated Protein Kinases.
- pharmacologie : Antinéoplasiques, Antirhumatismaux, Chloroquine, Inhibiteurs de protéines kinases, Phénylurées, Pyrazines.
- Altération de l'ADN, Autophagie, Carcinome pulmonaire non à petites cellules, Checkpoint kinase 1, Humains, Lignée cellulaire tumorale, Phosphorylation, Points de contrôle de la phase G2 du cycle cellulaire, Prolifération cellulaire, Réparation de l'ADN, Survie cellulaire, Tumeurs du poumon.
English descriptors
- KwdEn :
- Antineoplastic Agents (pharmacology), Antirheumatic Agents (pharmacology), Autophagy (drug effects), Carcinoma, Non-Small-Cell Lung, Caspases (metabolism), Cell Line, Tumor (drug effects), Cell Proliferation (drug effects), Cell Survival (drug effects), Checkpoint Kinase 1, Chloroquine (pharmacology), DNA Damage, DNA Repair (drug effects), G2 Phase Cell Cycle Checkpoints, Humans, Lung Neoplasms, MAP Kinase Kinase 4 (metabolism), Nuclear Proteins (metabolism), Phenylurea Compounds (pharmacology), Phosphorylation (drug effects), Protein Kinase Inhibitors (pharmacology), Protein Kinases (metabolism), Pyrazines (pharmacology), Serine (metabolism), p38 Mitogen-Activated Protein Kinases (metabolism).
- MESH :
- chemical , metabolism : Caspases, MAP Kinase Kinase 4, Nuclear Proteins, Protein Kinases, Serine, p38 Mitogen-Activated Protein Kinases.
- chemical , pharmacology : Antineoplastic Agents, Antirheumatic Agents, Chloroquine, Phenylurea Compounds, Protein Kinase Inhibitors, Pyrazines.
- drug effects : Autophagy, Cell Line, Tumor, Cell Proliferation, Cell Survival, DNA Repair, Phosphorylation.
- Carcinoma, Non-Small-Cell Lung, Checkpoint Kinase 1, DNA Damage, G2 Phase Cell Cycle Checkpoints, Humans, Lung Neoplasms.
Abstract
Chemotherapy- or radiotherapy-induced DNA damage activates the Chk1-dependent DNA damage response (DDR) and cell cycle checkpoints to facilitate cell survival. Numerous attempts have been made to identify specific Chk1 inhibitors to enhance the efficiency of chemotherapy or radiotherapy. In this study, we investigated the molecular mechanisms underlying the antitumor activity of LY2603618, a potent and selective small molecule inhibitor of Chk1 protein kinase, in human lung cancer cells. Treatment of cancer cells with LY2603618 caused cell cycle arrest in the G2/M phase. A marked induction of DDR, including the phosphorylation of ATM, Chk2, p53 and histone H2AX, was observed after LY2603618 treatment. LY2603618 inhibited Chk1 autophosphorylation (S296 Chk1) and increased DNA damage-mediated Chk1 phosphorylation (S345 Chk1). In addition, LY2603618-treated lung cancer cells transitioned from LC3-I to LC3-II, a hallmark of autophagy. Blocking autophagy with chloroquine (CQ) further enhanced LY2603618's inhibitory effect on cell viability/proliferation. LY2603618 also significantly increased p38 and c-Jun N-terminal kinase (JNK) phosphorylation. Pretreatment with the JNK inhibitor reduced cleavage of caspase-3 and PARP levels in LY2603618-treated cells. These results suggest the following: (i) the biological consequences of LY2603618 in lung cancer cells is associated with both inhibition of Chk1 phosphorylation on S296 and activation of the DNA damage response network; and (ii) the anticancer property of LY2603618 might be increased by inhibiting autophagy.
DOI: 10.1007/s10495-014-1010-3
PubMed: 24928205
Affiliations:
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Le document en format XML
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cells.</title><author><name sortKey="Wang, Feng Ze" sort="Wang, Feng Ze" uniqKey="Wang F" first="Feng-Ze" last="Wang">Feng-Ze Wang</name><affiliation wicri:level="1"><nlm:affiliation>School of Biological Science, Taishan Medical University, Taian, 271016, People's Republic of China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>School of Biological Science, Taishan Medical University, Taian, 271016</wicri:regionArea><wicri:noRegion>271016</wicri:noRegion></affiliation></author><author><name sortKey="Fei, Hong Rong" sort="Fei, Hong Rong" uniqKey="Fei H" first="Hong-Rong" last="Fei">Hong-Rong Fei</name></author><author><name sortKey="Cui, Ying Jie" sort="Cui, Ying Jie" uniqKey="Cui Y" first="Ying-Jie" last="Cui">Ying-Jie Cui</name></author><author><name sortKey="Sun, Ying Kun" sort="Sun, Ying Kun" uniqKey="Sun Y" first="Ying-Kun" last="Sun">Ying-Kun Sun</name></author><author><name sortKey="Li, Zhao Mei" sort="Li, Zhao Mei" uniqKey="Li Z" first="Zhao-Mei" last="Li">Zhao-Mei Li</name></author><author><name sortKey="Wang, Xue Ying" sort="Wang, Xue Ying" uniqKey="Wang X" first="Xue-Ying" last="Wang">Xue-Ying Wang</name></author><author><name sortKey="Yang, Xiao Yi" sort="Yang, Xiao Yi" uniqKey="Yang X" first="Xiao-Yi" last="Yang">Xiao-Yi Yang</name></author><author><name sortKey="Zhang, Ji Guo" sort="Zhang, Ji Guo" uniqKey="Zhang J" first="Ji-Guo" last="Zhang">Ji-Guo Zhang</name></author><author><name sortKey="Sun, Bao Liang" sort="Sun, Bao Liang" uniqKey="Sun B" first="Bao-Liang" last="Sun">Bao-Liang Sun</name></author></analytic><series><title level="j">Apoptosis : an international journal on programmed cell death</title><idno type="eISSN">1573-675X</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antineoplastic Agents (pharmacology)</term><term>Antirheumatic Agents (pharmacology)</term><term>Autophagy (drug effects)</term><term>Carcinoma, Non-Small-Cell Lung</term><term>Caspases (metabolism)</term><term>Cell Line, Tumor (drug effects)</term><term>Cell Proliferation (drug effects)</term><term>Cell Survival (drug effects)</term><term>Checkpoint Kinase 1</term><term>Chloroquine (pharmacology)</term><term>DNA Damage</term><term>DNA Repair (drug effects)</term><term>G2 Phase Cell Cycle Checkpoints</term><term>Humans</term><term>Lung Neoplasms</term><term>MAP Kinase Kinase 4 (metabolism)</term><term>Nuclear Proteins (metabolism)</term><term>Phenylurea Compounds (pharmacology)</term><term>Phosphorylation (drug effects)</term><term>Protein Kinase Inhibitors (pharmacology)</term><term>Protein Kinases (metabolism)</term><term>Pyrazines (pharmacology)</term><term>Serine (metabolism)</term><term>p38 Mitogen-Activated Protein Kinases (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Altération de l'ADN</term><term>Antinéoplasiques (pharmacologie)</term><term>Antirhumatismaux (pharmacologie)</term><term>Autophagie ()</term><term>Carcinome pulmonaire non à petites cellules</term><term>Caspases (métabolisme)</term><term>Checkpoint kinase 1</term><term>Chloroquine (pharmacologie)</term><term>Humains</term><term>Inhibiteurs de protéines kinases (pharmacologie)</term><term>Lignée cellulaire tumorale ()</term><term>MAP Kinase Kinase 4 (métabolisme)</term><term>Phosphorylation ()</term><term>Phénylurées (pharmacologie)</term><term>Points de contrôle de la phase G2 du cycle cellulaire</term><term>Prolifération cellulaire ()</term><term>Protein kinases (métabolisme)</term><term>Protéines nucléaires (métabolisme)</term><term>Pyrazines (pharmacologie)</term><term>Réparation de l'ADN ()</term><term>Survie cellulaire ()</term><term>Sérine (métabolisme)</term><term>Tumeurs du poumon</term><term>p38 Mitogen-Activated Protein Kinases (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" 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qualifier="pharmacologie" xml:lang="fr"><term>Antinéoplasiques</term><term>Antirhumatismaux</term><term>Chloroquine</term><term>Inhibiteurs de protéines kinases</term><term>Phénylurées</term><term>Pyrazines</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term><term>Checkpoint Kinase 1</term><term>DNA Damage</term><term>G2 Phase Cell Cycle Checkpoints</term><term>Humans</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Altération de l'ADN</term><term>Autophagie</term><term>Carcinome pulmonaire non à petites cellules</term><term>Checkpoint kinase 1</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Phosphorylation</term><term>Points de contrôle de la phase G2 du cycle cellulaire</term><term>Prolifération cellulaire</term><term>Réparation de l'ADN</term><term>Survie cellulaire</term><term>Tumeurs du poumon</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Chemotherapy- or radiotherapy-induced DNA damage activates the Chk1-dependent DNA damage response (DDR) and cell cycle checkpoints to facilitate cell survival. Numerous attempts have been made to identify specific Chk1 inhibitors to enhance the efficiency of chemotherapy or radiotherapy. In this study, we investigated the molecular mechanisms underlying the antitumor activity of LY2603618, a potent and selective small molecule inhibitor of Chk1 protein kinase, in human lung cancer cells. Treatment of cancer cells with LY2603618 caused cell cycle arrest in the G2/M phase. A marked induction of DDR, including the phosphorylation of ATM, Chk2, p53 and histone H2AX, was observed after LY2603618 treatment. LY2603618 inhibited Chk1 autophosphorylation (S296 Chk1) and increased DNA damage-mediated Chk1 phosphorylation (S345 Chk1). In addition, LY2603618-treated lung cancer cells transitioned from LC3-I to LC3-II, a hallmark of autophagy. Blocking autophagy with chloroquine (CQ) further enhanced LY2603618's inhibitory effect on cell viability/proliferation. LY2603618 also significantly increased p38 and c-Jun N-terminal kinase (JNK) phosphorylation. Pretreatment with the JNK inhibitor reduced cleavage of caspase-3 and PARP levels in LY2603618-treated cells. These results suggest the following: (i) the biological consequences of LY2603618 in lung cancer cells is associated with both inhibition of Chk1 phosphorylation on S296 and activation of the DNA damage response network; and (ii) the anticancer property of LY2603618 might be increased by inhibiting autophagy. </div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><noCountry><name sortKey="Cui, Ying Jie" sort="Cui, Ying Jie" uniqKey="Cui Y" first="Ying-Jie" last="Cui">Ying-Jie Cui</name><name sortKey="Fei, Hong Rong" sort="Fei, Hong Rong" uniqKey="Fei H" first="Hong-Rong" last="Fei">Hong-Rong Fei</name><name sortKey="Li, Zhao Mei" sort="Li, Zhao Mei" uniqKey="Li Z" first="Zhao-Mei" last="Li">Zhao-Mei Li</name><name sortKey="Sun, Bao Liang" sort="Sun, Bao Liang" uniqKey="Sun B" first="Bao-Liang" last="Sun">Bao-Liang Sun</name><name sortKey="Sun, Ying Kun" sort="Sun, Ying Kun" uniqKey="Sun Y" first="Ying-Kun" last="Sun">Ying-Kun Sun</name><name sortKey="Wang, Xue Ying" sort="Wang, Xue Ying" uniqKey="Wang X" first="Xue-Ying" last="Wang">Xue-Ying Wang</name><name sortKey="Yang, Xiao Yi" sort="Yang, Xiao Yi" uniqKey="Yang X" first="Xiao-Yi" last="Yang">Xiao-Yi Yang</name><name sortKey="Zhang, Ji Guo" sort="Zhang, Ji Guo" uniqKey="Zhang J" first="Ji-Guo" last="Zhang">Ji-Guo Zhang</name></noCountry><country name="République populaire de Chine"><noRegion><name sortKey="Wang, Feng Ze" sort="Wang, Feng Ze" uniqKey="Wang F" first="Feng-Ze" last="Wang">Feng-Ze Wang</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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