Lysosome Membrane Permeabilization and Disruption of the Molecular Target of Rapamycin (mTOR)-Lysosome Interaction Are Associated with the Inhibition of Lung Cancer Cell Proliferation by a Chloroquinoline Analog.
Identifieur interne : 000075 ( PubMed/Corpus ); précédent : 000074; suivant : 000076Lysosome Membrane Permeabilization and Disruption of the Molecular Target of Rapamycin (mTOR)-Lysosome Interaction Are Associated with the Inhibition of Lung Cancer Cell Proliferation by a Chloroquinoline Analog.
Auteurs : Juan Sironi ; Evelyn Aranda ; Lars Ulrik Nordstr M ; Edward L. SchwartzSource :
- Molecular pharmacology [ 1521-0111 ] ; 2019.
English descriptors
- KwdEn :
- Apoptosis (drug effects), Autophagy (drug effects), Cell Line, Tumor, Cell Proliferation (drug effects), Chloroquine (pharmacology), Chloroquinolinols (pharmacology), Humans, Lung Neoplasms (drug therapy), Lung Neoplasms (metabolism), Lysosomes (drug effects), Lysosomes (metabolism), Mechanistic Target of Rapamycin Complex 1 (metabolism), Membranes (drug effects), Permeability (drug effects), Phosphorylation (drug effects), Signal Transduction (drug effects), TOR Serine-Threonine Kinases (metabolism).
- MESH :
- chemical , metabolism : Mechanistic Target of Rapamycin Complex 1, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Chloroquine, Chloroquinolinols.
- drug effects : Apoptosis, Autophagy, Cell Proliferation, Lysosomes, Membranes, Permeability, Phosphorylation, Signal Transduction.
- drug therapy : Lung Neoplasms.
- metabolism : Lung Neoplasms, Lysosomes.
- Cell Line, Tumor, Humans.
Abstract
Lysosomes degrade cellular proteins and organelles and regulate cell signaling by providing a surface for the formation of critical protein complexes, notably molecular target of rapamycin (mTOR) complex 1 (mTORC1). Striking differences in the lysosomes of cancer versus normal cells suggest that they could be targets for drug development. Although the lysomotropic drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have been widely investigated, studies have focused on their ability to inhibit autophagy. We synthesized a novel compound, called EAD1, which is structurally related to CQ but is a 14-fold more potent inhibitor of cell proliferation. Here we find that EAD1 causes rapid relocation, membrane permeabilization (LMP), and deacidification of lysosomes, and it induces apoptosis and irreversibly blocks proliferation of human lung cancer H460, H520, H1299, HCC827, and H1703 cells. EAD1 causes dissociation of mTOR from lysosomes and increases mTOR's perinuclear versus cytoplasmic localization, changes previously shown to inactivate mTORC1. The effect on mTOR was not seen with HCQ, even at >10-fold greater concentrations. Phosphorylation of a downstream target of mTORC1, ribosomal protein S6, was inhibited by EAD1. Although EAD1 also inhibited autophagy, it retained full antiproliferative activity in autophagy-deficient H1650 lung cancer cells, which have a biallelic deletion of Atg7, and in H460 Atg7-knockout cells. As Atg7 is critical for the canonical autophagy pathway, it is likely that inhibition of autophagy is not how EAD1 inhibits cell proliferation. Further studies are needed to determine the relationship of LMP to mTORC1 disruption and their relative contributions to drug-induced cell death. These studies support the lysosome as an underexplored target for new drug development.
DOI: 10.1124/mol.118.113118
PubMed: 30409790
Links to Exploration step
pubmed:30409790Le document en format XML
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Schwartz</name><affiliation><nlm:affiliation>Departments of Medicine (Oncology) (J.S., E.A., E.L.S.) and Biochemistry (L.U.N.), Albert Einstein College of Medicine and the Einstein Cancer Center, Bronx, New York edward.schwartz@einstein.yu.edu.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2019">2019</date><idno type="RBID">pubmed:30409790</idno><idno type="pmid">30409790</idno><idno type="doi">10.1124/mol.118.113118</idno><idno type="wicri:Area/PubMed/Corpus">000075</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000075</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Lysosome Membrane Permeabilization and Disruption of the Molecular Target of Rapamycin (mTOR)-Lysosome Interaction Are Associated with the Inhibition of Lung Cancer Cell Proliferation by a Chloroquinoline Analog.</title><author><name sortKey="Sironi, Juan" sort="Sironi, Juan" uniqKey="Sironi J" first="Juan" last="Sironi">Juan Sironi</name><affiliation><nlm:affiliation>Departments of Medicine (Oncology) (J.S., E.A., E.L.S.) and Biochemistry (L.U.N.), Albert Einstein College of Medicine and the Einstein Cancer Center, Bronx, New York.</nlm:affiliation></affiliation></author><author><name sortKey="Aranda, Evelyn" sort="Aranda, Evelyn" uniqKey="Aranda E" first="Evelyn" last="Aranda">Evelyn Aranda</name><affiliation><nlm:affiliation>Departments of Medicine (Oncology) (J.S., E.A., E.L.S.) and Biochemistry (L.U.N.), Albert Einstein College of Medicine and the Einstein Cancer Center, Bronx, New York.</nlm:affiliation></affiliation></author><author><name sortKey="Nordstr M, Lars Ulrik" sort="Nordstr M, Lars Ulrik" uniqKey="Nordstr M L" first="Lars Ulrik" last="Nordstr M">Lars Ulrik Nordstr M</name><affiliation><nlm:affiliation>Departments of Medicine (Oncology) (J.S., E.A., E.L.S.) and Biochemistry (L.U.N.), Albert Einstein College of Medicine and the Einstein Cancer Center, Bronx, New York.</nlm:affiliation></affiliation></author><author><name sortKey="Schwartz, Edward L" sort="Schwartz, Edward L" uniqKey="Schwartz E" first="Edward L" last="Schwartz">Edward L. Schwartz</name><affiliation><nlm:affiliation>Departments of Medicine (Oncology) (J.S., E.A., E.L.S.) and Biochemistry (L.U.N.), Albert Einstein College of Medicine and the Einstein Cancer Center, Bronx, New York edward.schwartz@einstein.yu.edu.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Molecular pharmacology</title><idno type="eISSN">1521-0111</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Apoptosis (drug effects)</term><term>Autophagy (drug effects)</term><term>Cell Line, Tumor</term><term>Cell Proliferation (drug effects)</term><term>Chloroquine (pharmacology)</term><term>Chloroquinolinols (pharmacology)</term><term>Humans</term><term>Lung Neoplasms (drug therapy)</term><term>Lung Neoplasms (metabolism)</term><term>Lysosomes (drug effects)</term><term>Lysosomes (metabolism)</term><term>Mechanistic Target of Rapamycin Complex 1 (metabolism)</term><term>Membranes (drug effects)</term><term>Permeability (drug effects)</term><term>Phosphorylation (drug effects)</term><term>Signal Transduction (drug effects)</term><term>TOR Serine-Threonine Kinases (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Mechanistic Target of Rapamycin Complex 1</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Chloroquine</term><term>Chloroquinolinols</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term><term>Autophagy</term><term>Cell Proliferation</term><term>Lysosomes</term><term>Membranes</term><term>Permeability</term><term>Phosphorylation</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lung Neoplasms</term><term>Lysosomes</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term><term>Humans</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Lysosomes degrade cellular proteins and organelles and regulate cell signaling by providing a surface for the formation of critical protein complexes, notably molecular target of rapamycin (mTOR) complex 1 (mTORC1). Striking differences in the lysosomes of cancer versus normal cells suggest that they could be targets for drug development. Although the lysomotropic drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have been widely investigated, studies have focused on their ability to inhibit autophagy. We synthesized a novel compound, called EAD1, which is structurally related to CQ but is a 14-fold more potent inhibitor of cell proliferation. Here we find that EAD1 causes rapid relocation, membrane permeabilization (LMP), and deacidification of lysosomes, and it induces apoptosis and irreversibly blocks proliferation of human lung cancer H460, H520, H1299, HCC827, and H1703 cells. EAD1 causes dissociation of mTOR from lysosomes and increases mTOR's perinuclear versus cytoplasmic localization, changes previously shown to inactivate mTORC1. The effect on mTOR was not seen with HCQ, even at >10-fold greater concentrations. Phosphorylation of a downstream target of mTORC1, ribosomal protein S6, was inhibited by EAD1. Although EAD1 also inhibited autophagy, it retained full antiproliferative activity in autophagy-deficient H1650 lung cancer cells, which have a biallelic deletion of Atg7, and in H460 Atg7-knockout cells. As Atg7 is critical for the canonical autophagy pathway, it is likely that inhibition of autophagy is not how EAD1 inhibits cell proliferation. Further studies are needed to determine the relationship of LMP to mTORC1 disruption and their relative contributions to drug-induced cell death. These studies support the lysosome as an underexplored target for new drug development.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">30409790</PMID><DateCompleted><Year>2019</Year><Month>06</Month><Day>17</Day></DateCompleted><DateRevised><Year>2020</Year><Month>03</Month><Day>09</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1521-0111</ISSN><JournalIssue CitedMedium="Internet"><Volume>95</Volume><Issue>1</Issue><PubDate><Year>2019</Year><Month>01</Month></PubDate></JournalIssue><Title>Molecular pharmacology</Title><ISOAbbreviation>Mol. Pharmacol.</ISOAbbreviation></Journal><ArticleTitle>Lysosome Membrane Permeabilization and Disruption of the Molecular Target of Rapamycin (mTOR)-Lysosome Interaction Are Associated with the Inhibition of Lung Cancer Cell Proliferation by a Chloroquinoline Analog.</ArticleTitle><Pagination><MedlinePgn>127-138</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1124/mol.118.113118</ELocationID><Abstract><AbstractText>Lysosomes degrade cellular proteins and organelles and regulate cell signaling by providing a surface for the formation of critical protein complexes, notably molecular target of rapamycin (mTOR) complex 1 (mTORC1). Striking differences in the lysosomes of cancer versus normal cells suggest that they could be targets for drug development. Although the lysomotropic drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have been widely investigated, studies have focused on their ability to inhibit autophagy. We synthesized a novel compound, called EAD1, which is structurally related to CQ but is a 14-fold more potent inhibitor of cell proliferation. Here we find that EAD1 causes rapid relocation, membrane permeabilization (LMP), and deacidification of lysosomes, and it induces apoptosis and irreversibly blocks proliferation of human lung cancer H460, H520, H1299, HCC827, and H1703 cells. EAD1 causes dissociation of mTOR from lysosomes and increases mTOR's perinuclear versus cytoplasmic localization, changes previously shown to inactivate mTORC1. The effect on mTOR was not seen with HCQ, even at >10-fold greater concentrations. Phosphorylation of a downstream target of mTORC1, ribosomal protein S6, was inhibited by EAD1. Although EAD1 also inhibited autophagy, it retained full antiproliferative activity in autophagy-deficient H1650 lung cancer cells, which have a biallelic deletion of Atg7, and in H460 Atg7-knockout cells. As Atg7 is critical for the canonical autophagy pathway, it is likely that inhibition of autophagy is not how EAD1 inhibits cell proliferation. Further studies are needed to determine the relationship of LMP to mTORC1 disruption and their relative contributions to drug-induced cell death. These studies support the lysosome as an underexplored target for new drug development.</AbstractText><CopyrightInformation>Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Sironi</LastName><ForeName>Juan</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Departments of Medicine (Oncology) (J.S., E.A., E.L.S.) and Biochemistry (L.U.N.), Albert Einstein College of Medicine and the Einstein Cancer Center, Bronx, New York.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Aranda</LastName><ForeName>Evelyn</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Departments of Medicine (Oncology) (J.S., E.A., E.L.S.) and Biochemistry (L.U.N.), Albert Einstein College of Medicine and the Einstein Cancer Center, Bronx, New York.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nordstrøm</LastName><ForeName>Lars Ulrik</ForeName><Initials>LU</Initials><AffiliationInfo><Affiliation>Departments of Medicine (Oncology) (J.S., E.A., E.L.S.) and Biochemistry (L.U.N.), Albert Einstein College of Medicine and the Einstein Cancer Center, Bronx, New York.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schwartz</LastName><ForeName>Edward L</ForeName><Initials>EL</Initials><AffiliationInfo><Affiliation>Departments of Medicine (Oncology) (J.S., E.A., E.L.S.) and Biochemistry (L.U.N.), Albert Einstein College of Medicine and the Einstein Cancer Center, Bronx, New York edward.schwartz@einstein.yu.edu.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>KL2 TR001071</GrantID><Acronym>TR</Acronym><Agency>NCATS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P30 CA013330</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>TL1 TR001072</GrantID><Acronym>TR</Acronym><Agency>NCATS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>UL1 TR001073</GrantID><Acronym>TR</Acronym><Agency>NCATS NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2018</Year><Month>11</Month><Day>08</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Mol Pharmacol</MedlineTA><NlmUniqueID>0035623</NlmUniqueID><ISSNLinking>0026-895X</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D002739">Chloroquinolinols</NameOfSubstance></Chemical><Chemical><RegistryNumber>886U3H6UFF</RegistryNumber><NameOfSubstance UI="D002738">Chloroquine</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="C546842">MTOR protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="D058570">TOR Serine-Threonine Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D000076222">Mechanistic Target of Rapamycin Complex 1</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D017209" MajorTopicYN="N">Apoptosis</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001343" MajorTopicYN="N">Autophagy</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D049109" MajorTopicYN="N">Cell Proliferation</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002738" MajorTopicYN="N">Chloroquine</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002739" MajorTopicYN="N">Chloroquinolinols</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008175" MajorTopicYN="N">Lung Neoplasms</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008247" MajorTopicYN="N">Lysosomes</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000076222" MajorTopicYN="N">Mechanistic Target of Rapamycin Complex 1</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008566" MajorTopicYN="N">Membranes</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010539" MajorTopicYN="N">Permeability</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010766" MajorTopicYN="N">Phosphorylation</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2018</Year><Month>05</Month><Day>23</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2018</Year><Month>10</Month><Day>31</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2018</Year><Month>11</Month><Day>10</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2019</Year><Month>6</Month><Day>18</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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