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Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells

The specific 26S proteasome inhibitor bortezomib (BZ) potently induces autophagy, endoplasmic reticulum (ER) stress and apoptosis in multiple myeloma (MM) cell lines (U266, IM-9 and RPMI8226). The macrolide antibiotics including concanamycin A, erythromycin (EM), clarithromycin (CAM) and azithromyci...

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Autores principales: MORIYA, SHOTA, CHE, XIAO-FANG, KOMATSU, SEIICHIRO, ABE, AKIHISA, KAWAGUCHI, TOMOHIRO, GOTOH, AKIHIKO, INAZU, MASATO, TOMODA, AKIO, MIYAZAWA, KEISUKE
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661227/
https://www.ncbi.nlm.nih.gov/pubmed/23546223
http://dx.doi.org/10.3892/ijo.2013.1870
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author MORIYA, SHOTA
CHE, XIAO-FANG
KOMATSU, SEIICHIRO
ABE, AKIHISA
KAWAGUCHI, TOMOHIRO
GOTOH, AKIHIKO
INAZU, MASATO
TOMODA, AKIO
MIYAZAWA, KEISUKE
author_facet MORIYA, SHOTA
CHE, XIAO-FANG
KOMATSU, SEIICHIRO
ABE, AKIHISA
KAWAGUCHI, TOMOHIRO
GOTOH, AKIHIKO
INAZU, MASATO
TOMODA, AKIO
MIYAZAWA, KEISUKE
author_sort MORIYA, SHOTA
collection PubMed
description The specific 26S proteasome inhibitor bortezomib (BZ) potently induces autophagy, endoplasmic reticulum (ER) stress and apoptosis in multiple myeloma (MM) cell lines (U266, IM-9 and RPMI8226). The macrolide antibiotics including concanamycin A, erythromycin (EM), clarithromycin (CAM) and azithromycin (AZM) all blocked autophagy flux, as assessed by intracellular accumulation of LC3B-II and p62. Combined treatment of BZ and CAM or AZM enhanced cytotoxicity in MM cell lines, although treatment with either CAM or AZM alone exhibited almost no cytotoxicity. This combination also substantially enhanced aggresome formation, intracellular ubiquitinated proteins and induced the proapoptotic transcription factor CHOP (CADD153). Expression levels of the proapoptotic genes transcriptionally regulated by CHOP (BIM, BAX, DR5 and TRB3) were all enhanced by combined treatment with BZ plus CAM, compared with treatment with each reagent alone. Like the MM cell lines, the CHOP(+/+) murine embryonic fibroblast (MEF) cell line exhibited enhanced cytotoxicity and upregulation of CHOP and its transcriptional targets with a combination of BZ and one of the macrolides. In contrast, CHOP(−/−) MEF cells exhibited resistance against BZ and almost completely canceled enhanced cytotoxicity with a combination of BZ and a macrolide. These data suggest that ER stress-mediated CHOP induction is involved in pronounced cytotoxicity. Simultaneously targeting two major intracellular protein degradation systems such as the ubiquitin-proteasome system by BZ and the autophagy-lysosome system by a macrolide antibiotic enhances ER stress-mediated apoptosis in MM cells. This result suggests the therapeutic possibility of using a macrolide antibiotic with a proteasome inhibitor for MM therapy.
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spelling pubmed-36612272013-05-22 Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells MORIYA, SHOTA CHE, XIAO-FANG KOMATSU, SEIICHIRO ABE, AKIHISA KAWAGUCHI, TOMOHIRO GOTOH, AKIHIKO INAZU, MASATO TOMODA, AKIO MIYAZAWA, KEISUKE Int J Oncol Articles The specific 26S proteasome inhibitor bortezomib (BZ) potently induces autophagy, endoplasmic reticulum (ER) stress and apoptosis in multiple myeloma (MM) cell lines (U266, IM-9 and RPMI8226). The macrolide antibiotics including concanamycin A, erythromycin (EM), clarithromycin (CAM) and azithromycin (AZM) all blocked autophagy flux, as assessed by intracellular accumulation of LC3B-II and p62. Combined treatment of BZ and CAM or AZM enhanced cytotoxicity in MM cell lines, although treatment with either CAM or AZM alone exhibited almost no cytotoxicity. This combination also substantially enhanced aggresome formation, intracellular ubiquitinated proteins and induced the proapoptotic transcription factor CHOP (CADD153). Expression levels of the proapoptotic genes transcriptionally regulated by CHOP (BIM, BAX, DR5 and TRB3) were all enhanced by combined treatment with BZ plus CAM, compared with treatment with each reagent alone. Like the MM cell lines, the CHOP(+/+) murine embryonic fibroblast (MEF) cell line exhibited enhanced cytotoxicity and upregulation of CHOP and its transcriptional targets with a combination of BZ and one of the macrolides. In contrast, CHOP(−/−) MEF cells exhibited resistance against BZ and almost completely canceled enhanced cytotoxicity with a combination of BZ and a macrolide. These data suggest that ER stress-mediated CHOP induction is involved in pronounced cytotoxicity. Simultaneously targeting two major intracellular protein degradation systems such as the ubiquitin-proteasome system by BZ and the autophagy-lysosome system by a macrolide antibiotic enhances ER stress-mediated apoptosis in MM cells. This result suggests the therapeutic possibility of using a macrolide antibiotic with a proteasome inhibitor for MM therapy. D.A. Spandidos 2013-03-28 /pmc/articles/PMC3661227/ /pubmed/23546223 http://dx.doi.org/10.3892/ijo.2013.1870 Text en Copyright © 2013, Spandidos Publications http://creativecommons.org/licenses/by/3.0 This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.
spellingShingle Articles
MORIYA, SHOTA
CHE, XIAO-FANG
KOMATSU, SEIICHIRO
ABE, AKIHISA
KAWAGUCHI, TOMOHIRO
GOTOH, AKIHIKO
INAZU, MASATO
TOMODA, AKIO
MIYAZAWA, KEISUKE
Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells
title Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells
title_full Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells
title_fullStr Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells
title_full_unstemmed Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells
title_short Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells
title_sort macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated chop induction in myeloma cells
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661227/
https://www.ncbi.nlm.nih.gov/pubmed/23546223
http://dx.doi.org/10.3892/ijo.2013.1870
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