Metastatic cells are preferentially vulnerable to lysosomal inhibition.
Identifieur interne : 000C24 ( Main/Exploration ); précédent : 000C23; suivant : 000C25Metastatic cells are preferentially vulnerable to lysosomal inhibition.
Auteurs : Michael J. Morgan [États-Unis] ; Brent E. Fitzwalter [États-Unis] ; Charles R. Owens [États-Unis] ; Rani K. Powers [États-Unis] ; Joseph L. Sottnik [États-Unis] ; Graciela Gamez [États-Unis] ; James C. Costello [États-Unis] ; Dan Theodorescu [États-Unis] ; Andrew Thorburn [États-Unis]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 1091-6490 ] ; 2018.
Descripteurs français
- KwdFr :
- Animaux, Chloroquine (pharmacologie), Humains, Lignée cellulaire tumorale, Lysosomes (anatomopathologie), Lysosomes (métabolisme), Macrolides (pharmacologie), Métastase tumorale, Protéines d'inhibition de la différenciation (biosynthèse), Protéines tumorales (biosynthèse), Régulation de l'expression des gènes tumoraux (), Résistance aux médicaments antinéoplasiques (), Souris, Tumeurs de la vessie urinaire (anatomopathologie), Tumeurs de la vessie urinaire (génétique), Tumeurs de la vessie urinaire (métabolisme), Tumeurs de la vessie urinaire (traitement médicamenteux), Tumeurs du poumon (anatomopathologie), Tumeurs du poumon (métabolisme), Tumeurs du poumon (secondaire), Tumeurs du poumon (traitement médicamenteux).
- MESH :
- anatomopathologie : Lysosomes, Tumeurs de la vessie urinaire, Tumeurs du poumon.
- biosynthèse : Protéines d'inhibition de la différenciation, Protéines tumorales.
- génétique : Tumeurs de la vessie urinaire.
- métabolisme : Lysosomes, Tumeurs de la vessie urinaire, Tumeurs du poumon.
- pharmacologie : Chloroquine, Macrolides.
- secondaire : Tumeurs du poumon.
- traitement médicamenteux : Tumeurs de la vessie urinaire, Tumeurs du poumon.
- Animaux, Humains, Lignée cellulaire tumorale, Métastase tumorale, Régulation de l'expression des gènes tumoraux, Résistance aux médicaments antinéoplasiques, Souris.
English descriptors
- KwdEn :
- Animals, Cell Line, Tumor, Chloroquine (pharmacology), Drug Resistance, Neoplasm (drug effects), Gene Expression Regulation, Neoplastic (drug effects), Humans, Inhibitor of Differentiation Proteins (biosynthesis), Lung Neoplasms (drug therapy), Lung Neoplasms (metabolism), Lung Neoplasms (pathology), Lung Neoplasms (secondary), Lysosomes (metabolism), Lysosomes (pathology), Macrolides (pharmacology), Mice, Neoplasm Metastasis, Neoplasm Proteins (biosynthesis), Urinary Bladder Neoplasms (drug therapy), Urinary Bladder Neoplasms (genetics), Urinary Bladder Neoplasms (metabolism), Urinary Bladder Neoplasms (pathology).
- MESH :
- chemical , biosynthesis : Inhibitor of Differentiation Proteins, Neoplasm Proteins.
- chemical , pharmacology : Chloroquine, Macrolides.
- drug effects : Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic.
- drug therapy : Lung Neoplasms, Urinary Bladder Neoplasms.
- genetics : Urinary Bladder Neoplasms.
- metabolism : Lung Neoplasms, Lysosomes, Urinary Bladder Neoplasms.
- pathology : Lung Neoplasms, Lysosomes, Urinary Bladder Neoplasms.
- secondary : Lung Neoplasms.
- Animals, Cell Line, Tumor, Humans, Mice, Neoplasm Metastasis.
Abstract
Molecular alterations that confer phenotypic advantages to tumors can also expose specific therapeutic vulnerabilities. To search for potential treatments that would selectively affect metastatic cells, we examined the sensitivity of lineage-related human bladder cancer cell lines with different lung colonization abilities to chloroquine (CQ) or bafilomycin A1, which are inhibitors of lysosome function and autophagy. Both CQ and bafilomycin A1 were more cytotoxic in vitro to highly metastatic cells compared with their less metastatic counterparts. Genetic inactivation of macroautophagy regulators and lysosomal proteins indicated that this was due to greater reliance on the lysosome but not upon macroautophagy. To identify the mechanism underlying these effects, we generated cells resistant to CQ in vitro. Surprisingly, selection for in vitro CQ resistance was sufficient to alter gene expression patterns such that unsupervised cluster analysis of whole-transcriptome data indicated that selection for CQ resistance alone created tumor cells that were more similar to the poorly metastatic parental cells from which the metastatic cells were derived; importantly, these tumor cells also had diminished metastatic ability in vivo. These effects were mediated in part by differential expression of the transcriptional regulator ID4 (inhibitor of DNA binding 4); depletion of ID4 both promoted in vitro CQ sensitivity and restored lung colonization and metastasis of CQ-resistant cells. These data demonstrate that selection for metastasis ability confers selective vulnerability to lysosomal inhibitors and identify ID4 as a potential biomarker for the use of lysosomal inhibitors to reduce metastasis in patients.
DOI: 10.1073/pnas.1706526115
PubMed: 30127018
Affiliations:
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Le document en format XML
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<series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Cell Line, Tumor</term>
<term>Chloroquine (pharmacology)</term>
<term>Drug Resistance, Neoplasm (drug effects)</term>
<term>Gene Expression Regulation, Neoplastic (drug effects)</term>
<term>Humans</term>
<term>Inhibitor of Differentiation Proteins (biosynthesis)</term>
<term>Lung Neoplasms (drug therapy)</term>
<term>Lung Neoplasms (metabolism)</term>
<term>Lung Neoplasms (pathology)</term>
<term>Lung Neoplasms (secondary)</term>
<term>Lysosomes (metabolism)</term>
<term>Lysosomes (pathology)</term>
<term>Macrolides (pharmacology)</term>
<term>Mice</term>
<term>Neoplasm Metastasis</term>
<term>Neoplasm Proteins (biosynthesis)</term>
<term>Urinary Bladder Neoplasms (drug therapy)</term>
<term>Urinary Bladder Neoplasms (genetics)</term>
<term>Urinary Bladder Neoplasms (metabolism)</term>
<term>Urinary Bladder Neoplasms (pathology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Chloroquine (pharmacologie)</term>
<term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Lysosomes (anatomopathologie)</term>
<term>Lysosomes (métabolisme)</term>
<term>Macrolides (pharmacologie)</term>
<term>Métastase tumorale</term>
<term>Protéines d'inhibition de la différenciation (biosynthèse)</term>
<term>Protéines tumorales (biosynthèse)</term>
<term>Régulation de l'expression des gènes tumoraux ()</term>
<term>Résistance aux médicaments antinéoplasiques ()</term>
<term>Souris</term>
<term>Tumeurs de la vessie urinaire (anatomopathologie)</term>
<term>Tumeurs de la vessie urinaire (génétique)</term>
<term>Tumeurs de la vessie urinaire (métabolisme)</term>
<term>Tumeurs de la vessie urinaire (traitement médicamenteux)</term>
<term>Tumeurs du poumon (anatomopathologie)</term>
<term>Tumeurs du poumon (métabolisme)</term>
<term>Tumeurs du poumon (secondaire)</term>
<term>Tumeurs du poumon (traitement médicamenteux)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Inhibitor of Differentiation Proteins</term>
<term>Neoplasm Proteins</term>
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<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Chloroquine</term>
<term>Macrolides</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Lysosomes</term>
<term>Tumeurs de la vessie urinaire</term>
<term>Tumeurs du poumon</term>
</keywords>
<keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>Protéines d'inhibition de la différenciation</term>
<term>Protéines tumorales</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Drug Resistance, Neoplasm</term>
<term>Gene Expression Regulation, Neoplastic</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Lung Neoplasms</term>
<term>Urinary Bladder Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Urinary Bladder Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Tumeurs de la vessie urinaire</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lung Neoplasms</term>
<term>Lysosomes</term>
<term>Urinary Bladder Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Lysosomes</term>
<term>Tumeurs de la vessie urinaire</term>
<term>Tumeurs du poumon</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Lung Neoplasms</term>
<term>Lysosomes</term>
<term>Urinary Bladder Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Chloroquine</term>
<term>Macrolides</term>
</keywords>
<keywords scheme="MESH" qualifier="secondaire" xml:lang="fr"><term>Tumeurs du poumon</term>
</keywords>
<keywords scheme="MESH" qualifier="secondary" xml:lang="en"><term>Lung Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Tumeurs de la vessie urinaire</term>
<term>Tumeurs du poumon</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cell Line, Tumor</term>
<term>Humans</term>
<term>Mice</term>
<term>Neoplasm Metastasis</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Métastase tumorale</term>
<term>Régulation de l'expression des gènes tumoraux</term>
<term>Résistance aux médicaments antinéoplasiques</term>
<term>Souris</term>
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<front><div type="abstract" xml:lang="en">Molecular alterations that confer phenotypic advantages to tumors can also expose specific therapeutic vulnerabilities. To search for potential treatments that would selectively affect metastatic cells, we examined the sensitivity of lineage-related human bladder cancer cell lines with different lung colonization abilities to chloroquine (CQ) or bafilomycin A<sub>1</sub>
, which are inhibitors of lysosome function and autophagy. Both CQ and bafilomycin A<sub>1</sub>
were more cytotoxic in vitro to highly metastatic cells compared with their less metastatic counterparts. Genetic inactivation of macroautophagy regulators and lysosomal proteins indicated that this was due to greater reliance on the lysosome but not upon macroautophagy. To identify the mechanism underlying these effects, we generated cells resistant to CQ in vitro. Surprisingly, selection for in vitro CQ resistance was sufficient to alter gene expression patterns such that unsupervised cluster analysis of whole-transcriptome data indicated that selection for CQ resistance alone created tumor cells that were more similar to the poorly metastatic parental cells from which the metastatic cells were derived; importantly, these tumor cells also had diminished metastatic ability in vivo. These effects were mediated in part by differential expression of the transcriptional regulator ID4 (inhibitor of DNA binding 4); depletion of ID4 both promoted in vitro CQ sensitivity and restored lung colonization and metastasis of CQ-resistant cells. These data demonstrate that selection for metastasis ability confers selective vulnerability to lysosomal inhibitors and identify ID4 as a potential biomarker for the use of lysosomal inhibitors to reduce metastasis in patients.</div>
</front>
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<affiliations><list><country><li>États-Unis</li>
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<tree><country name="États-Unis"><noRegion><name sortKey="Morgan, Michael J" sort="Morgan, Michael J" uniqKey="Morgan M" first="Michael J" last="Morgan">Michael J. Morgan</name>
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<name sortKey="Costello, James C" sort="Costello, James C" uniqKey="Costello J" first="James C" last="Costello">James C. Costello</name>
<name sortKey="Fitzwalter, Brent E" sort="Fitzwalter, Brent E" uniqKey="Fitzwalter B" first="Brent E" last="Fitzwalter">Brent E. Fitzwalter</name>
<name sortKey="Gamez, Graciela" sort="Gamez, Graciela" uniqKey="Gamez G" first="Graciela" last="Gamez">Graciela Gamez</name>
<name sortKey="Owens, Charles R" sort="Owens, Charles R" uniqKey="Owens C" first="Charles R" last="Owens">Charles R. Owens</name>
<name sortKey="Powers, Rani K" sort="Powers, Rani K" uniqKey="Powers R" first="Rani K" last="Powers">Rani K. Powers</name>
<name sortKey="Sottnik, Joseph L" sort="Sottnik, Joseph L" uniqKey="Sottnik J" first="Joseph L" last="Sottnik">Joseph L. Sottnik</name>
<name sortKey="Theodorescu, Dan" sort="Theodorescu, Dan" uniqKey="Theodorescu D" first="Dan" last="Theodorescu">Dan Theodorescu</name>
<name sortKey="Thorburn, Andrew" sort="Thorburn, Andrew" uniqKey="Thorburn A" first="Andrew" last="Thorburn">Andrew Thorburn</name>
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