The HSP70 Modulator MAL3-101 Inhibits Merkel Cell Carcinoma
Identifieur interne : 000F01 ( Main/Exploration ); précédent : 000F00; suivant : 000F02The HSP70 Modulator MAL3-101 Inhibits Merkel Cell Carcinoma
Auteurs : Christian Adam [Allemagne] ; Anne Baeurle [Allemagne] ; Jeffrey L. Brodsky [États-Unis] ; Peter Wipf [États-Unis] ; David Schrama [Autriche] ; Jürgen Christian Becker [Autriche] ; Roland Houben [Allemagne]Source :
- PLoS ONE [ 1932-6203 ] ; 2014.
Descripteurs français
- KwdFr :
- Animaux, Antigènes des virus oncogènes (génétique), Antigènes des virus oncogènes (métabolisme), Antinéoplasiques (pharmacologie), Carcinome à cellules de Merkel (génétique), Carcinome à cellules de Merkel (métabolisme), Carcinome à cellules de Merkel (traitement médicamenteux), Carcinome à cellules de Merkel (virologie), Humains, Infections à polyomavirus (génétique), Infections à polyomavirus (métabolisme), Infections à polyomavirus (traitement médicamenteux), Infections à virus oncogènes (anatomopathologie), Infections à virus oncogènes (génétique), Infections à virus oncogènes (métabolisme), Infections à virus oncogènes (traitement médicamenteux), Lignée cellulaire tumorale, Polyomavirus (génétique), Polyomavirus (métabolisme), Protéines du choc thermique HSP70 (antagonistes et inhibiteurs), Protéines du choc thermique HSP70 (biosynthèse), Protéines du choc thermique HSP70 (génétique), Protéines tumorales (antagonistes et inhibiteurs), Protéines tumorales (génétique), Protéines tumorales (métabolisme), Régulation de l'expression des gènes tumoraux (), Régulation de l'expression des gènes tumoraux (génétique), Souris, Souris de lignée NOD, Tests d'activité antitumorale sur modèle de xénogreffe, Transformation cellulaire virale (), Transformation cellulaire virale (génétique).
- MESH :
- anatomopathologie : Infections à virus oncogènes.
- antagonistes et inhibiteurs : Protéines du choc thermique HSP70, Protéines tumorales.
- biosynthèse : Protéines du choc thermique HSP70.
- génétique : Antigènes des virus oncogènes, Carcinome à cellules de Merkel, Infections à polyomavirus, Infections à virus oncogènes, Polyomavirus, Protéines du choc thermique HSP70, Protéines tumorales, Régulation de l'expression des gènes tumoraux, Transformation cellulaire virale.
- métabolisme : Antigènes des virus oncogènes, Carcinome à cellules de Merkel, Infections à polyomavirus, Infections à virus oncogènes, Polyomavirus, Protéines tumorales.
- pharmacologie : Antinéoplasiques.
- traitement médicamenteux : Carcinome à cellules de Merkel, Infections à polyomavirus, Infections à virus oncogènes.
- virologie : Carcinome à cellules de Merkel.
- Animaux, Humains, Lignée cellulaire tumorale, Régulation de l'expression des gènes tumoraux, Souris, Souris de lignée NOD, Tests d'activité antitumorale sur modèle de xénogreffe, Transformation cellulaire virale.
English descriptors
- KwdEn :
- Animals, Antigens, Viral, Tumor (genetics), Antigens, Viral, Tumor (metabolism), Antineoplastic Agents (pharmacology), Carcinoma, Merkel Cell (drug therapy), Carcinoma, Merkel Cell (genetics), Carcinoma, Merkel Cell (metabolism), Carcinoma, Merkel Cell (virology), Cell Line, Tumor, Cell Transformation, Viral (drug effects), Cell Transformation, Viral (genetics), Gene Expression Regulation, Neoplastic (drug effects), Gene Expression Regulation, Neoplastic (genetics), HSP70 Heat-Shock Proteins (antagonists & inhibitors), HSP70 Heat-Shock Proteins (biosynthesis), HSP70 Heat-Shock Proteins (genetics), Humans, Mice, Mice, Inbred NOD, Neoplasm Proteins (antagonists & inhibitors), Neoplasm Proteins (genetics), Neoplasm Proteins (metabolism), Polyomavirus (genetics), Polyomavirus (metabolism), Polyomavirus Infections (drug therapy), Polyomavirus Infections (genetics), Polyomavirus Infections (metabolism), Tumor Virus Infections (drug therapy), Tumor Virus Infections (genetics), Tumor Virus Infections (metabolism), Tumor Virus Infections (pathology), Xenograft Model Antitumor Assays.
- MESH :
- chemical , antagonists & inhibitors : HSP70 Heat-Shock Proteins, Neoplasm Proteins.
- chemical , biosynthesis : HSP70 Heat-Shock Proteins.
- chemical , genetics : Antigens, Viral, Tumor, HSP70 Heat-Shock Proteins, Neoplasm Proteins.
- chemical , metabolism : Antigens, Viral, Tumor, Neoplasm Proteins.
- chemical , pharmacology : Antineoplastic Agents.
- drug effects : Cell Transformation, Viral, Gene Expression Regulation, Neoplastic.
- drug therapy : Carcinoma, Merkel Cell, Polyomavirus Infections, Tumor Virus Infections.
- genetics : Carcinoma, Merkel Cell, Cell Transformation, Viral, Gene Expression Regulation, Neoplastic, Polyomavirus, Polyomavirus Infections, Tumor Virus Infections.
- metabolism : Carcinoma, Merkel Cell, Polyomavirus, Polyomavirus Infections, Tumor Virus Infections.
- pathology : Tumor Virus Infections.
- virology : Carcinoma, Merkel Cell.
- Animals, Cell Line, Tumor, Humans, Mice, Mice, Inbred NOD, Xenograft Model Antitumor Assays.
Abstract
Merkel Cell Carcinoma (MCC) is a rare and highly aggressive neuroendocrine skin cancer for which no effective treatment is available. MCC represents a human cancer with the best experimental evidence for a causal role of a polyoma virus. Large T antigens (LTA) encoded by polyoma viruses are oncoproteins, which are thought to require support of cellular heat shock protein 70 (HSP70) to exert their transforming activity. Here we evaluated the capability of MAL3-101, a synthetic HSP70 inhibitor, to limit proliferation and survival of various MCC cell lines. Remarkably, MAL3-101 treatment resulted in considerable apoptosis in 5 out of 7 MCC cell lines. While this effect was not associated with the viral status of the MCC cells, quantitative mRNA expression analysis of the known HSP70 isoforms revealed a significant correlation between MAL3-101 sensitivity and HSC70 expression, the most prominent isoform in all cell lines. Moreover, MAL3-101 also exhibited
Url:
DOI: 10.1371/journal.pone.0092041
PubMed: 24694787
PubMed Central: 3973671
Affiliations:
- Allemagne, Autriche, États-Unis
- Bavière, District de Basse-Franconie, Pennsylvanie
- Pittsburgh, Wurtzbourg
- Université de Pittsburgh
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Le document en format XML
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uniqKey="Becker J" first="Jürgen Christian" last="Becker">Jürgen Christian Becker</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Division of General Dermatology, Medical University of Graz, Graz, Austria</addr-line></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Division of General Dermatology, Medical University of Graz, Graz</wicri:regionArea><wicri:noRegion>Graz</wicri:noRegion></affiliation></author><author><name sortKey="Houben, Roland" sort="Houben, Roland" uniqKey="Houben R" first="Roland" last="Houben">Roland Houben</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Department of Dermatology, University Hospital of Würzburg, Würzburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Dermatology, University Hospital of Würzburg, Würzburg</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Basse-Franconie</region><settlement type="city">Wurtzbourg</settlement></placeName></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antigens, Viral, Tumor (genetics)</term><term>Antigens, Viral, Tumor (metabolism)</term><term>Antineoplastic Agents (pharmacology)</term><term>Carcinoma, Merkel Cell (drug therapy)</term><term>Carcinoma, Merkel Cell (genetics)</term><term>Carcinoma, Merkel Cell (metabolism)</term><term>Carcinoma, Merkel Cell (virology)</term><term>Cell Line, Tumor</term><term>Cell Transformation, Viral (drug effects)</term><term>Cell Transformation, Viral (genetics)</term><term>Gene Expression Regulation, Neoplastic (drug effects)</term><term>Gene Expression Regulation, Neoplastic (genetics)</term><term>HSP70 Heat-Shock Proteins (antagonists & inhibitors)</term><term>HSP70 Heat-Shock Proteins (biosynthesis)</term><term>HSP70 Heat-Shock Proteins (genetics)</term><term>Humans</term><term>Mice</term><term>Mice, Inbred NOD</term><term>Neoplasm Proteins (antagonists & inhibitors)</term><term>Neoplasm Proteins (genetics)</term><term>Neoplasm Proteins (metabolism)</term><term>Polyomavirus (genetics)</term><term>Polyomavirus (metabolism)</term><term>Polyomavirus Infections (drug therapy)</term><term>Polyomavirus Infections (genetics)</term><term>Polyomavirus Infections (metabolism)</term><term>Tumor Virus Infections (drug therapy)</term><term>Tumor Virus Infections (genetics)</term><term>Tumor Virus Infections (metabolism)</term><term>Tumor Virus Infections (pathology)</term><term>Xenograft Model Antitumor Assays</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Antigènes des virus oncogènes (génétique)</term><term>Antigènes des virus oncogènes (métabolisme)</term><term>Antinéoplasiques (pharmacologie)</term><term>Carcinome à cellules de Merkel (génétique)</term><term>Carcinome à cellules de Merkel (métabolisme)</term><term>Carcinome à cellules de Merkel (traitement médicamenteux)</term><term>Carcinome à cellules de Merkel (virologie)</term><term>Humains</term><term>Infections à polyomavirus (génétique)</term><term>Infections à polyomavirus (métabolisme)</term><term>Infections à polyomavirus (traitement médicamenteux)</term><term>Infections à virus oncogènes (anatomopathologie)</term><term>Infections à virus oncogènes (génétique)</term><term>Infections à virus oncogènes (métabolisme)</term><term>Infections à virus oncogènes (traitement médicamenteux)</term><term>Lignée cellulaire tumorale</term><term>Polyomavirus (génétique)</term><term>Polyomavirus (métabolisme)</term><term>Protéines du choc thermique HSP70 (antagonistes et inhibiteurs)</term><term>Protéines du choc thermique HSP70 (biosynthèse)</term><term>Protéines du choc thermique HSP70 (génétique)</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 ()</term><term>Régulation de l'expression des gènes tumoraux (génétique)</term><term>Souris</term><term>Souris de lignée NOD</term><term>Tests d'activité antitumorale sur modèle de xénogreffe</term><term>Transformation cellulaire virale ()</term><term>Transformation cellulaire virale (génétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>HSP70 Heat-Shock Proteins</term><term>Neoplasm Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>HSP70 Heat-Shock Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Antigens, Viral, Tumor</term><term>HSP70 Heat-Shock Proteins</term><term>Neoplasm Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antigens, Viral, Tumor</term><term>Neoplasm Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Agents</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Infections à virus oncogènes</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines du choc thermique HSP70</term><term>Protéines tumorales</term></keywords><keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>Protéines du choc thermique HSP70</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Transformation, Viral</term><term>Gene Expression Regulation, Neoplastic</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Carcinoma, Merkel Cell</term><term>Polyomavirus Infections</term><term>Tumor Virus Infections</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Carcinoma, Merkel Cell</term><term>Cell Transformation, Viral</term><term>Gene Expression Regulation, Neoplastic</term><term>Polyomavirus</term><term>Polyomavirus Infections</term><term>Tumor Virus Infections</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Antigènes des virus oncogènes</term><term>Carcinome à cellules de Merkel</term><term>Infections à polyomavirus</term><term>Infections à virus oncogènes</term><term>Polyomavirus</term><term>Protéines du choc thermique HSP70</term><term>Protéines tumorales</term><term>Régulation de l'expression des gènes tumoraux</term><term>Transformation cellulaire virale</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Carcinoma, Merkel Cell</term><term>Polyomavirus</term><term>Polyomavirus Infections</term><term>Tumor Virus Infections</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Antigènes des virus oncogènes</term><term>Carcinome à cellules de Merkel</term><term>Infections à polyomavirus</term><term>Infections à virus oncogènes</term><term>Polyomavirus</term><term>Protéines tumorales</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Tumor Virus Infections</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antinéoplasiques</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Carcinome à cellules de Merkel</term><term>Infections à polyomavirus</term><term>Infections à virus oncogènes</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Carcinome à cellules de Merkel</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Carcinoma, Merkel Cell</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line, Tumor</term><term>Humans</term><term>Mice</term><term>Mice, Inbred NOD</term><term>Xenograft Model Antitumor Assays</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Régulation de l'expression des gènes tumoraux</term><term>Souris</term><term>Souris de lignée NOD</term><term>Tests d'activité antitumorale sur modèle de xénogreffe</term><term>Transformation cellulaire virale</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Merkel Cell Carcinoma (MCC) is a rare and highly aggressive neuroendocrine skin cancer for which no effective treatment is available. MCC represents a human cancer with the best experimental evidence for a causal role of a polyoma virus. Large T antigens (LTA) encoded by polyoma viruses are oncoproteins, which are thought to require support of cellular heat shock protein 70 (HSP70) to exert their transforming activity. Here we evaluated the capability of MAL3-101, a synthetic HSP70 inhibitor, to limit proliferation and survival of various MCC cell lines. Remarkably, MAL3-101 treatment resulted in considerable apoptosis in 5 out of 7 MCC cell lines. While this effect was not associated with the viral status of the MCC cells, quantitative mRNA expression analysis of the known HSP70 isoforms revealed a significant correlation between MAL3-101 sensitivity and HSC70 expression, the most prominent isoform in all cell lines. Moreover, MAL3-101 also exhibited <italic>in vivo</italic> antitumor activity in an MCC xenograft model suggesting that this substance or related compounds are potential therapeutics for the treatment of MCC in the future.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Howard, Ra" uniqKey="Howard R">RA Howard</name></author><author><name sortKey="Dores, Gm" uniqKey="Dores G">GM Dores</name></author><author><name sortKey="Curtis, Re" uniqKey="Curtis R">RE Curtis</name></author><author><name sortKey="Anderson, Wf" uniqKey="Anderson W">WF Anderson</name></author><author><name sortKey="Travis, Lb" uniqKey="Travis L">LB Travis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wieland, U" uniqKey="Wieland U">U Wieland</name></author><author><name sortKey="Kreuter, A" uniqKey="Kreuter A">A Kreuter</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Agelli, M" 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sortKey="Willmes, C" uniqKey="Willmes C">C Willmes</name></author><author><name sortKey="Adam, C" uniqKey="Adam C">C Adam</name></author><author><name sortKey="Alb, M" uniqKey="Alb M">M Alb</name></author><author><name sortKey="Volkert, L" uniqKey="Volkert L">L Volkert</name></author><author><name sortKey="Houben, R" uniqKey="Houben R">R Houben</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Allemagne</li><li>Autriche</li><li>États-Unis</li></country><region><li>Bavière</li><li>District de Basse-Franconie</li><li>Pennsylvanie</li></region><settlement><li>Pittsburgh</li><li>Wurtzbourg</li></settlement><orgName><li>Université de Pittsburgh</li></orgName></list><tree><country name="Allemagne"><region name="Bavière"><name sortKey="Adam, Christian" sort="Adam, Christian" uniqKey="Adam C" first="Christian" last="Adam">Christian Adam</name></region><name sortKey="Baeurle, Anne" sort="Baeurle, Anne" uniqKey="Baeurle A" first="Anne" last="Baeurle">Anne Baeurle</name><name sortKey="Houben, Roland" sort="Houben, Roland" uniqKey="Houben R" first="Roland" last="Houben">Roland Houben</name></country><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Brodsky, Jeffrey L" sort="Brodsky, Jeffrey L" uniqKey="Brodsky J" first="Jeffrey L." last="Brodsky">Jeffrey L. Brodsky</name></region><name sortKey="Wipf, Peter" sort="Wipf, Peter" uniqKey="Wipf P" first="Peter" last="Wipf">Peter Wipf</name></country><country name="Autriche"><noRegion><name sortKey="Schrama, David" sort="Schrama, David" uniqKey="Schrama D" first="David" last="Schrama">David Schrama</name></noRegion><name sortKey="Becker, Jurgen Christian" sort="Becker, Jurgen Christian" uniqKey="Becker J" first="Jürgen Christian" last="Becker">Jürgen Christian Becker</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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