Regorafenib inhibits colorectal tumor growth through PUMA-mediated apoptosis
Identifieur interne : 001698 ( Main/Exploration ); précédent : 001697; suivant : 001699Regorafenib inhibits colorectal tumor growth through PUMA-mediated apoptosis
Auteurs : Dongshi Chen [États-Unis] ; Liang Wei [États-Unis] ; Jian Yu [États-Unis] ; Lin Zhang [États-Unis]Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research [ 1078-0432 ] ; 2014.
Descripteurs français
- KwdFr :
- Activation de la transcription (), Animaux, Antinéoplasiques (pharmacologie), Apoptose (), Apoptose (génétique), Facteur de transcription NF-kappa B (métabolisme), Femelle, Glycogen Synthase Kinase 3 (métabolisme), Glycogen synthase kinase 3 beta, Humains, Liaison aux protéines, Lignée cellulaire tumorale, Modèles animaux de maladie humaine, Néovascularisation pathologique (génétique), Phénylurées (pharmacologie), Protéines proto-oncogènes (génétique), Protéines proto-oncogènes (métabolisme), Protéines régulatrices de l'apoptose (génétique), Protéines régulatrices de l'apoptose (métabolisme), Pyridines (pharmacologie), Régions promotrices (génétique), Régulation de l'expression des gènes tumoraux (), Régulation positive, Résistance aux médicaments antinéoplasiques (génétique), Souris, Tests d'activité antitumorale sur modèle de xénogreffe, Tumeurs colorectales (anatomopathologie), Tumeurs colorectales (génétique).
- MESH :
- anatomopathologie : Tumeurs colorectales.
- génétique : Apoptose, Néovascularisation pathologique, Protéines proto-oncogènes, Protéines régulatrices de l'apoptose, Résistance aux médicaments antinéoplasiques, Tumeurs colorectales.
- métabolisme : Facteur de transcription NF-kappa B, Glycogen Synthase Kinase 3, Protéines proto-oncogènes, Protéines régulatrices de l'apoptose.
- pharmacologie : Antinéoplasiques, Phénylurées, Pyridines.
- Activation de la transcription, Animaux, Apoptose, Femelle, Glycogen synthase kinase 3 beta, Humains, Liaison aux protéines, Lignée cellulaire tumorale, Modèles animaux de maladie humaine, Régions promotrices (génétique), Régulation de l'expression des gènes tumoraux, Régulation positive, Souris, Tests d'activité antitumorale sur modèle de xénogreffe.
English descriptors
- KwdEn :
- Animals, Antineoplastic Agents (pharmacology), Apoptosis (drug effects), Apoptosis (genetics), Apoptosis Regulatory Proteins (genetics), Apoptosis Regulatory Proteins (metabolism), Cell Line, Tumor, Colorectal Neoplasms (genetics), Colorectal Neoplasms (pathology), Disease Models, Animal, Drug Resistance, Neoplasm (genetics), Female, Gene Expression Regulation, Neoplastic (drug effects), Glycogen Synthase Kinase 3 (metabolism), Glycogen Synthase Kinase 3 beta, Humans, Mice, NF-kappa B (metabolism), Neovascularization, Pathologic (genetics), Phenylurea Compounds (pharmacology), Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins (genetics), Proto-Oncogene Proteins (metabolism), Pyridines (pharmacology), Transcriptional Activation (drug effects), Up-Regulation, Xenograft Model Antitumor Assays.
- MESH :
- chemical , genetics : Apoptosis Regulatory Proteins, Proto-Oncogene Proteins.
- chemical , metabolism : Apoptosis Regulatory Proteins, Glycogen Synthase Kinase 3, NF-kappa B, Proto-Oncogene Proteins.
- chemical , pharmacology : Antineoplastic Agents, Phenylurea Compounds, Pyridines.
- drug effects : Apoptosis, Gene Expression Regulation, Neoplastic, Transcriptional Activation.
- genetics : Apoptosis, Colorectal Neoplasms, Drug Resistance, Neoplasm, Neovascularization, Pathologic.
- pathology : Colorectal Neoplasms.
- Animals, Cell Line, Tumor, Disease Models, Animal, Female, Glycogen Synthase Kinase 3 beta, Humans, Mice, Promoter Regions, Genetic, Protein Binding, Up-Regulation, Xenograft Model Antitumor Assays.
Abstract
Regorafenib, a multi-kinase inhibitor targeting the Ras/Raf/MEK/ERK pathway, has recently been approved for the treatment of metastatic colorectal cancer (CRC). However, the mechanisms of action of regorafenib in CRC cells have been unclear. We investigated how regorafenib suppresses CRC cell growth and potentiates effects of other chemotherapeutic drugs.
We determined whether and how regorafenib induces the expression of PUMA, a p53 target and a critical mediator of apoptosis in CRC cells. We also investigated whether PUMA is necessary for the killing and chemosensitization effects of regorafenib in CRC cells. Furthermore, xenograft tumors were used to test if PUMA mediates the
We found that regorafenib treatment induces PUMA in CRC cells irrespective of p53 status through the NF-κB pathway following ERK inhibition and glycogen synthase kinase 3β (GSK3β) activation. Upregulation of PUMA is correlated with apoptosis induction in different CRC cell lines. PUMA is necessary for regorafenib-induced apoptosis in CRC cells. Chemosensitization by regorafenib is mediated by enhanced PUMA induction through different pathways. Furthermore, deficiency in PUMA abrogates the
Our results demonstrate a key role of PUMA in mediating the anticancer effects of regorafenib in CRC cells. They suggest that PUMA induction can be used as an indicator of regorafenib sensitivity, and also provide a rationale for manipulating the apoptotic machinery to improve the therapeutic efficacy of regorafenib and other targeted drugs.
Url:
DOI: 10.1158/1078-0432.CCR-13-2944
PubMed: 24763611
PubMed Central: 4079733
Affiliations:
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<term>Antineoplastic Agents (pharmacology)</term>
<term>Apoptosis (drug effects)</term>
<term>Apoptosis (genetics)</term>
<term>Apoptosis Regulatory Proteins (genetics)</term>
<term>Apoptosis Regulatory Proteins (metabolism)</term>
<term>Cell Line, Tumor</term>
<term>Colorectal Neoplasms (genetics)</term>
<term>Colorectal Neoplasms (pathology)</term>
<term>Disease Models, Animal</term>
<term>Drug Resistance, Neoplasm (genetics)</term>
<term>Female</term>
<term>Gene Expression Regulation, Neoplastic (drug effects)</term>
<term>Glycogen Synthase Kinase 3 (metabolism)</term>
<term>Glycogen Synthase Kinase 3 beta</term>
<term>Humans</term>
<term>Mice</term>
<term>NF-kappa B (metabolism)</term>
<term>Neovascularization, Pathologic (genetics)</term>
<term>Phenylurea Compounds (pharmacology)</term>
<term>Promoter Regions, Genetic</term>
<term>Protein Binding</term>
<term>Proto-Oncogene Proteins (genetics)</term>
<term>Proto-Oncogene Proteins (metabolism)</term>
<term>Pyridines (pharmacology)</term>
<term>Transcriptional Activation (drug effects)</term>
<term>Up-Regulation</term>
<term>Xenograft Model Antitumor Assays</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Activation de la transcription ()</term>
<term>Animaux</term>
<term>Antinéoplasiques (pharmacologie)</term>
<term>Apoptose ()</term>
<term>Apoptose (génétique)</term>
<term>Facteur de transcription NF-kappa B (métabolisme)</term>
<term>Femelle</term>
<term>Glycogen Synthase Kinase 3 (métabolisme)</term>
<term>Glycogen synthase kinase 3 beta</term>
<term>Humains</term>
<term>Liaison aux protéines</term>
<term>Lignée cellulaire tumorale</term>
<term>Modèles animaux de maladie humaine</term>
<term>Néovascularisation pathologique (génétique)</term>
<term>Phénylurées (pharmacologie)</term>
<term>Protéines proto-oncogènes (génétique)</term>
<term>Protéines proto-oncogènes (métabolisme)</term>
<term>Protéines régulatrices de l'apoptose (génétique)</term>
<term>Protéines régulatrices de l'apoptose (métabolisme)</term>
<term>Pyridines (pharmacologie)</term>
<term>Régions promotrices (génétique)</term>
<term>Régulation de l'expression des gènes tumoraux ()</term>
<term>Régulation positive</term>
<term>Résistance aux médicaments antinéoplasiques (génétique)</term>
<term>Souris</term>
<term>Tests d'activité antitumorale sur modèle de xénogreffe</term>
<term>Tumeurs colorectales (anatomopathologie)</term>
<term>Tumeurs colorectales (génétique)</term>
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<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Apoptosis Regulatory Proteins</term>
<term>Proto-Oncogene Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Apoptosis Regulatory Proteins</term>
<term>Glycogen Synthase Kinase 3</term>
<term>NF-kappa B</term>
<term>Proto-Oncogene Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Agents</term>
<term>Phenylurea Compounds</term>
<term>Pyridines</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Tumeurs colorectales</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term>
<term>Gene Expression Regulation, Neoplastic</term>
<term>Transcriptional Activation</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Apoptosis</term>
<term>Colorectal Neoplasms</term>
<term>Drug Resistance, Neoplasm</term>
<term>Neovascularization, Pathologic</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Apoptose</term>
<term>Néovascularisation pathologique</term>
<term>Protéines proto-oncogènes</term>
<term>Protéines régulatrices de l'apoptose</term>
<term>Résistance aux médicaments antinéoplasiques</term>
<term>Tumeurs colorectales</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Facteur de transcription NF-kappa B</term>
<term>Glycogen Synthase Kinase 3</term>
<term>Protéines proto-oncogènes</term>
<term>Protéines régulatrices de l'apoptose</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Colorectal Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antinéoplasiques</term>
<term>Phénylurées</term>
<term>Pyridines</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cell Line, Tumor</term>
<term>Disease Models, Animal</term>
<term>Female</term>
<term>Glycogen Synthase Kinase 3 beta</term>
<term>Humans</term>
<term>Mice</term>
<term>Promoter Regions, Genetic</term>
<term>Protein Binding</term>
<term>Up-Regulation</term>
<term>Xenograft Model Antitumor Assays</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Activation de la transcription</term>
<term>Animaux</term>
<term>Apoptose</term>
<term>Femelle</term>
<term>Glycogen synthase kinase 3 beta</term>
<term>Humains</term>
<term>Liaison aux protéines</term>
<term>Lignée cellulaire tumorale</term>
<term>Modèles animaux de maladie humaine</term>
<term>Régions promotrices (génétique)</term>
<term>Régulation de l'expression des gènes tumoraux</term>
<term>Régulation positive</term>
<term>Souris</term>
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<front><div type="abstract" xml:lang="en"><sec id="S1"><title>Purpose</title>
<p id="P1">Regorafenib, a multi-kinase inhibitor targeting the Ras/Raf/MEK/ERK pathway, has recently been approved for the treatment of metastatic colorectal cancer (CRC). However, the mechanisms of action of regorafenib in CRC cells have been unclear. We investigated how regorafenib suppresses CRC cell growth and potentiates effects of other chemotherapeutic drugs.</p>
</sec>
<sec id="S2"><title>Experimental Design</title>
<p id="P2">We determined whether and how regorafenib induces the expression of PUMA, a p53 target and a critical mediator of apoptosis in CRC cells. We also investigated whether PUMA is necessary for the killing and chemosensitization effects of regorafenib in CRC cells. Furthermore, xenograft tumors were used to test if PUMA mediates the <italic>in vivo</italic>
antitumor, antiangiogenic and chemosensitization effects of regorafenib.</p>
</sec>
<sec id="S3"><title>Results</title>
<p id="P3">We found that regorafenib treatment induces PUMA in CRC cells irrespective of p53 status through the NF-κB pathway following ERK inhibition and glycogen synthase kinase 3β (GSK3β) activation. Upregulation of PUMA is correlated with apoptosis induction in different CRC cell lines. PUMA is necessary for regorafenib-induced apoptosis in CRC cells. Chemosensitization by regorafenib is mediated by enhanced PUMA induction through different pathways. Furthermore, deficiency in PUMA abrogates the <italic>in vivo</italic>
antitumor, antiangiogenic and chemosensitization effects of regorafenib.</p>
</sec>
<sec id="S4"><title>Conclusions</title>
<p id="P4">Our results demonstrate a key role of PUMA in mediating the anticancer effects of regorafenib in CRC cells. They suggest that PUMA induction can be used as an indicator of regorafenib sensitivity, and also provide a rationale for manipulating the apoptotic machinery to improve the therapeutic efficacy of regorafenib and other targeted drugs.</p>
</sec>
</div>
</front>
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<name sortKey="Chen, Dongshi" sort="Chen, Dongshi" uniqKey="Chen D" first="Dongshi" last="Chen">Dongshi Chen</name>
<name sortKey="Wei, Liang" sort="Wei, Liang" uniqKey="Wei L" first="Liang" last="Wei">Liang Wei</name>
<name sortKey="Wei, Liang" sort="Wei, Liang" uniqKey="Wei L" first="Liang" last="Wei">Liang Wei</name>
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<name sortKey="Yu, Jian" sort="Yu, Jian" uniqKey="Yu J" first="Jian" last="Yu">Jian Yu</name>
<name sortKey="Zhang, Lin" sort="Zhang, Lin" uniqKey="Zhang L" first="Lin" last="Zhang">Lin Zhang</name>
<name sortKey="Zhang, Lin" sort="Zhang, Lin" uniqKey="Zhang L" first="Lin" last="Zhang">Lin Zhang</name>
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