SERCA and P-glycoprotein inhibition and ATP depletion are necessary for celastrol-induced autophagic cell death and collateral sensitivity in multidrug-resistant tumor cells

Publication type:
Journal article
Metadata:
Autoren
  • Su-Wei Xu
  • Betty Yuen Kwan Law
  • Steven Li Qun Qu
  • Sami Hamdoun
  • Juan Chen
  • Wei Zhang
  • Jian-Ru Guo
  • An-Guo Wu
  • Simon Wing Fai Mok
  • David Wei Zhang
  • Chenglai Xia
  • Yoshikazu Sugimoto
  • Thomas Efferth
  • Liang Liu
  • Vincent Kam Wai Wong
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000521515600018&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.phrs.2020.104660
Externe Identifier
  • Clarivate Analytics Document Solution ID: KW9PM
  • PubMed Identifier: 31982489
ISSN
1043-6618
Zeitschrift
PHARMACOLOGICAL RESEARCH
Schlüsselwörter
  • SERCA inhibitor
  • P-gp inhibitor
  • Celastrol
  • Autophagic cell death
  • Collateral sensitivity
  • Multidrug resistance
  • Apoptosis-resistant cancer
Artikelnummer
ARTN 104660
Datum der Veröffentlichung
2020
Status
Published
Titel
SERCA and P-glycoprotein inhibition and ATP depletion are necessary for celastrol-induced autophagic cell death and collateral sensitivity in multidrug-resistant tumor cells
Sub types
  • Article
Ausgabe der Zeitschrift
153

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Su-Wei Xu
  • Betty Yuen Kwan Law
  • Steven Li Qun Qu
  • Sami Hamdoun
  • Juan Chen
  • Wei Zhang
  • Jian-Ru Guo
  • An-Guo Wu
  • Simon Wing Fai Mok
  • David Wei Zhang
  • Chenglai Xia
  • Yoshikazu Sugimoto
  • Thomas Efferth
  • Liang Liu
  • Vincent Kam Wai Wong
DOI
10.1016/j.phrs.2020.104660
ISSN
1043-6618
Zeitschrift
Pharmacological Research
Sprache
en
Artikelnummer
104660
Paginierung
104660 - 104660
Datum der Veröffentlichung
2020
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.phrs.2020.104660
Datum der Datenerfassung
2020
Titel
SERCA and P-glycoprotein inhibition and ATP depletion are necessary for celastrol-induced autophagic cell death and collateral sensitivity in multidrug-resistant tumor cells
Ausgabe der Zeitschrift
153

Data source: Crossref

Abstract
Multidrug resistance (MDR) represents an obstacle in anti-cancer therapy. MDR is caused by multiple mechanisms, involving ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), which reduces intracellular drug levels to sub-therapeutic concentrations. Therefore, sensitizing agents retaining effectiveness against apoptosis- or drug-resistant cancers are desired for the treatment of MDR cancers. The sarcoplasmic/endoplasmic reticulum Ca<sup>2+</sup> ATPase (SERCA) pump is an emerging target to overcome MDR, because of its continuous expression and because the calcium transport function is crucial to the survival of tumor cells. Previous studies showed that SERCA inhibitors exhibit anti-cancer effects in Bax-Bak-deficient, apoptosis-resistant and MDR cancers, whereas specific P-gp inhibitors reverse the MDR phenotype of cancer cells by blocking efflux of chemotherapeutic agents. Here, we unraveled SERCA and P-gp as double targets of the triterpenoid, celastrol to reverse MDR. Celastrol inhibited both SERCA and P-gp to stimulate calcium-mediated autophagy and ATP depletion, thereby induced collateral sensitivity in MDR cancer cells. In vivo studies further confirmed that celastrol suppressed tumor growth and metastasis by SERCA-mediated calcium mobilization. To the best of our knowledge, our findings demonstrate collateral sensitivity in MDR cancer cells by simultaneous inhibition of SERCA and P-gp for the first time.
Addresses
  • State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau; Department of Basic Medicine of Zhuhai Health School, Zhuhai, China.
Autoren
  • Su-Wei Xu
  • Betty Yuen Kwan Law
  • Steven Li Qun Qu
  • Sami Hamdoun
  • Juan Chen
  • Wei Zhang
  • Jian-Ru Guo
  • An-Guo Wu
  • Simon Wing Fai Mok
  • David Wei Zhang
  • Chenglai Xia
  • Yoshikazu Sugimoto
  • Thomas Efferth
  • Liang Liu
  • Vincent Kam Wai Wong
DOI
10.1016/j.phrs.2020.104660
eISSN
1096-1186
Externe Identifier
  • PubMed Identifier: 31982489
Funding acknowledgements
  • Foshan Medicine Dengfeng Project of China:
  • Macao Science and Technology Development Fund:
Open access
false
ISSN
1043-6618
Zeitschrift
Pharmacological research
Schlüsselwörter
  • Cell Line, Tumor
  • Hepatocytes
  • Animals
  • Mice, Inbred C57BL
  • Humans
  • Lung Neoplasms
  • Triterpenes
  • Adenosine Triphosphate
  • Antineoplastic Agents
  • Xenograft Model Antitumor Assays
  • Drug Resistance, Multiple
  • Cell Survival
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Autophagy
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Pentacyclic Triterpenes
  • Autophagy-Related Protein 7
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
Sprache
eng
Medium
Print-Electronic
Online publication date
2020
Paginierung
104660
Datum der Veröffentlichung
2020
Status
Published
Datum der Datenerfassung
2020
Titel
SERCA and P-glycoprotein inhibition and ATP depletion are necessary for celastrol-induced autophagic cell death and collateral sensitivity in multidrug-resistant tumor cells.
Sub types
  • Research Support, Non-U.S. Gov't
  • Journal Article
Ausgabe der Zeitschrift
153

Data source: Europe PubMed Central

Abstract
Multidrug resistance (MDR) represents an obstacle in anti-cancer therapy. MDR is caused by multiple mechanisms, involving ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), which reduces intracellular drug levels to sub-therapeutic concentrations. Therefore, sensitizing agents retaining effectiveness against apoptosis- or drug-resistant cancers are desired for the treatment of MDR cancers. The sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) pump is an emerging target to overcome MDR, because of its continuous expression and because the calcium transport function is crucial to the survival of tumor cells. Previous studies showed that SERCA inhibitors exhibit anti-cancer effects in Bax-Bak-deficient, apoptosis-resistant and MDR cancers, whereas specific P-gp inhibitors reverse the MDR phenotype of cancer cells by blocking efflux of chemotherapeutic agents. Here, we unraveled SERCA and P-gp as double targets of the triterpenoid, celastrol to reverse MDR. Celastrol inhibited both SERCA and P-gp to stimulate calcium-mediated autophagy and ATP depletion, thereby induced collateral sensitivity in MDR cancer cells. In vivo studies further confirmed that celastrol suppressed tumor growth and metastasis by SERCA-mediated calcium mobilization. To the best of our knowledge, our findings demonstrate collateral sensitivity in MDR cancer cells by simultaneous inhibition of SERCA and P-gp for the first time.
Date of acceptance
2020
Autoren
  • Su-Wei Xu
  • Betty Yuen Kwan Law
  • Steven Li Qun Qu
  • Sami Hamdoun
  • Juan Chen
  • Wei Zhang
  • Jian-Ru Guo
  • An-Guo Wu
  • Simon Wing Fai Mok
  • David Wei Zhang
  • Chenglai Xia
  • Yoshikazu Sugimoto
  • Thomas Efferth
  • Liang Liu
  • Vincent Kam Wai Wong
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/31982489
DOI
10.1016/j.phrs.2020.104660
eISSN
1096-1186
Zeitschrift
Pharmacol Res
Schlüsselwörter
  • Apoptosis-resistant cancer
  • Autophagic cell death
  • Celastrol
  • Collateral sensitivity
  • Multidrug resistance
  • P-gp inhibitor
  • SERCA inhibitor
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Adenosine Triphosphate
  • Animals
  • Antineoplastic Agents
  • Autophagy
  • Autophagy-Related Protein 7
  • Cell Line, Tumor
  • Cell Survival
  • Dose-Response Relationship, Drug
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Hepatocytes
  • Humans
  • Lung Neoplasms
  • Mice, Inbred C57BL
  • Pentacyclic Triterpenes
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Triterpenes
  • Xenograft Model Antitumor Assays
Sprache
eng
Country
Netherlands
Paginierung
104660
PII
S1043-6618(19)32539-3
Datum der Veröffentlichung
2020
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2021
Titel
SERCA and P-glycoprotein inhibition and ATP depletion are necessary for celastrol-induced autophagic cell death and collateral sensitivity in multidrug-resistant tumor cells.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
153

Data source: PubMed

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