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Simultaneous proteasome and autophagy inhibition synergistically enhances cytotoxicity of doxorubicin in breast cancer cells

Ubiquitin-proteasome system (UPS) and autophagy are interconnected proteolysis pathways implicated in doxorubicin resistance of breast cancer cells. Following anticancer treatments, autophagy either plays a cytoprotective role or augments treatment-induced cytotoxicity. However, the role of autophag...

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Main Authors: Loh, Jian Sheng, Abdul Rahim, Nusaibah, Tor, Yin Sim, Foo, Jhi Biau
格式: Article
出版: Wiley 2022
主題:
QH301 Biology
在線閱讀:http://eprints.um.edu.my/42257/
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spelling my.um.eprints.422572023-10-10T00:39:33Z http://eprints.um.edu.my/42257/ Simultaneous proteasome and autophagy inhibition synergistically enhances cytotoxicity of doxorubicin in breast cancer cells Loh, Jian Sheng Abdul Rahim, Nusaibah Tor, Yin Sim Foo, Jhi Biau QH301 Biology Ubiquitin-proteasome system (UPS) and autophagy are interconnected proteolysis pathways implicated in doxorubicin resistance of breast cancer cells. Following anticancer treatments, autophagy either plays a cytoprotective role or augments treatment-induced cytotoxicity. However, the role of autophagy in breast cancer cells cotreated with doxorubicin and ixazomib remains unclear. The expression of autophagy proteins (LC3A/B and Beclin-1) and UPS protein (ubiquitin) in MDA-MB-231 and MCF-7 cells following doxorubicin, ixazomib, and/or hydroxychloroquine were determined by western blot. The combinatorial effects and combination index (CI) of triple-combination were determined by cell viability assay and CompuSyn software, respectively. Doxorubicin and ixazomib cotreatment increased Beclin-1 (3.8- and 3.5-fold) and LC3-II expression (13.5- and 1.9-fold) in MDA-MB-231 and MCF-7 cells, respectively. Adding lysosomal inhibitor hydroxychloroquine to doxorubicin and ixazomib further increased LC3-II expression to 45.0- and 16.5-fold in MDA-MB-231 and MCF-7 cells, respectively, confirming autophagy induction. The triple-combination synergistically inhibited cell growth, achieving CI 0.672 and 0.157 in MDA-MB-231 and MCF-7 cells, respectively. The triple-combination also induced ubiquitinated proteins accumulation (2.5-fold and 3.0-fold) in MDA-MB-231 and MCF-7 cells, respectively. These results suggest that the autophagy induced by doxorubicin and ixazomib cotreatment serves cytoprotective role in breast cancer cells. Simultaneous UPS and autophagy inhibition synergistically enhanced doxorubicin-mediated cytotoxicity. Wiley 2022-06 Article PeerReviewed Loh, Jian Sheng and Abdul Rahim, Nusaibah and Tor, Yin Sim and Foo, Jhi Biau (2022) Simultaneous proteasome and autophagy inhibition synergistically enhances cytotoxicity of doxorubicin in breast cancer cells. Cell Biochemistry and Function, 40 (4). pp. 403-416. ISSN 0263-6484, DOI https://doi.org/10.1002/cbf.3704 <https://doi.org/10.1002/cbf.3704>. 10.1002/cbf.3704
institution Universiti Malaya
building UM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaya
content_source UM Research Repository
url_provider http://eprints.um.edu.my/
topic QH301 Biology
spellingShingle QH301 Biology
Loh, Jian Sheng
Abdul Rahim, Nusaibah
Tor, Yin Sim
Foo, Jhi Biau
Simultaneous proteasome and autophagy inhibition synergistically enhances cytotoxicity of doxorubicin in breast cancer cells
description Ubiquitin-proteasome system (UPS) and autophagy are interconnected proteolysis pathways implicated in doxorubicin resistance of breast cancer cells. Following anticancer treatments, autophagy either plays a cytoprotective role or augments treatment-induced cytotoxicity. However, the role of autophagy in breast cancer cells cotreated with doxorubicin and ixazomib remains unclear. The expression of autophagy proteins (LC3A/B and Beclin-1) and UPS protein (ubiquitin) in MDA-MB-231 and MCF-7 cells following doxorubicin, ixazomib, and/or hydroxychloroquine were determined by western blot. The combinatorial effects and combination index (CI) of triple-combination were determined by cell viability assay and CompuSyn software, respectively. Doxorubicin and ixazomib cotreatment increased Beclin-1 (3.8- and 3.5-fold) and LC3-II expression (13.5- and 1.9-fold) in MDA-MB-231 and MCF-7 cells, respectively. Adding lysosomal inhibitor hydroxychloroquine to doxorubicin and ixazomib further increased LC3-II expression to 45.0- and 16.5-fold in MDA-MB-231 and MCF-7 cells, respectively, confirming autophagy induction. The triple-combination synergistically inhibited cell growth, achieving CI 0.672 and 0.157 in MDA-MB-231 and MCF-7 cells, respectively. The triple-combination also induced ubiquitinated proteins accumulation (2.5-fold and 3.0-fold) in MDA-MB-231 and MCF-7 cells, respectively. These results suggest that the autophagy induced by doxorubicin and ixazomib cotreatment serves cytoprotective role in breast cancer cells. Simultaneous UPS and autophagy inhibition synergistically enhanced doxorubicin-mediated cytotoxicity.
format Article
author Loh, Jian Sheng
Abdul Rahim, Nusaibah
Tor, Yin Sim
Foo, Jhi Biau
author_facet Loh, Jian Sheng
Abdul Rahim, Nusaibah
Tor, Yin Sim
Foo, Jhi Biau
author_sort Loh, Jian Sheng
title Simultaneous proteasome and autophagy inhibition synergistically enhances cytotoxicity of doxorubicin in breast cancer cells
title_short Simultaneous proteasome and autophagy inhibition synergistically enhances cytotoxicity of doxorubicin in breast cancer cells
title_full Simultaneous proteasome and autophagy inhibition synergistically enhances cytotoxicity of doxorubicin in breast cancer cells
title_fullStr Simultaneous proteasome and autophagy inhibition synergistically enhances cytotoxicity of doxorubicin in breast cancer cells
title_full_unstemmed Simultaneous proteasome and autophagy inhibition synergistically enhances cytotoxicity of doxorubicin in breast cancer cells
title_sort simultaneous proteasome and autophagy inhibition synergistically enhances cytotoxicity of doxorubicin in breast cancer cells
publisher Wiley
publishDate 2022
url http://eprints.um.edu.my/42257/
_version_ 1781704617094021120
score 13.251813

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