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Targeting Oxidative Phosphorylation Reverses Drug Resistance in Cancer Cells by Blocking Autophagy Recycling

The greatest challenge in cancer therapy is posed by drug-resistant recurrence following treatment. Anticancer chemotherapy is largely focused on targeting the rapid proliferation and biosynthesis of cancer cells. This strategy has the potential to trigger autophagy, enabling cancer cell survival th...

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Autores principales: Lee, Jae-Seon, Lee, Ho, Jang, Hyonchol, Woo, Sang Myung, Park, Jong Bae, Lee, Seon-Hyeong, Kang, Joon Hee, Kim, Hee Yeon, Song, Jaewhan, Kim, Soo-Youl
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565066/
https://www.ncbi.nlm.nih.gov/pubmed/32883024
http://dx.doi.org/10.3390/cells9092013
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author Lee, Jae-Seon
Lee, Ho
Jang, Hyonchol
Woo, Sang Myung
Park, Jong Bae
Lee, Seon-Hyeong
Kang, Joon Hee
Kim, Hee Yeon
Song, Jaewhan
Kim, Soo-Youl
author_facet Lee, Jae-Seon
Lee, Ho
Jang, Hyonchol
Woo, Sang Myung
Park, Jong Bae
Lee, Seon-Hyeong
Kang, Joon Hee
Kim, Hee Yeon
Song, Jaewhan
Kim, Soo-Youl
author_sort Lee, Jae-Seon
collection PubMed
description The greatest challenge in cancer therapy is posed by drug-resistant recurrence following treatment. Anticancer chemotherapy is largely focused on targeting the rapid proliferation and biosynthesis of cancer cells. This strategy has the potential to trigger autophagy, enabling cancer cell survival through the recycling of molecules and energy essential for biosynthesis, leading to drug resistance. Autophagy recycling contributes amino acids and ATP to restore mTOR complex 1 (mTORC1) activity, which leads to cell survival. However, autophagy with mTORC1 activation can be stalled by reducing the ATP level. We have previously shown that cytosolic NADH production supported by aldehyde dehydrogenase (ALDH) is critical for supplying ATP through oxidative phosphorylation (OxPhos) in cancer cell mitochondria. Inhibitors of the mitochondrial complex I of the OxPhos electron transfer chain and ALDH significantly reduce the ATP level selectively in cancer cells, terminating autophagy triggered by anticancer drug treatment. With the aim of overcoming drug resistance, we investigated combining the inhibition of mitochondrial complex I, using phenformin, and ALDH, using gossypol, with anticancer drug treatment. Here, we show that OxPhos targeting combined with anticancer drugs acts synergistically to enhance the anticancer effect in mouse xenograft models of various cancers, which suggests a potential therapeutic approach for drug-resistant cancer.
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spelling pubmed-75650662020-10-26 Targeting Oxidative Phosphorylation Reverses Drug Resistance in Cancer Cells by Blocking Autophagy Recycling Lee, Jae-Seon Lee, Ho Jang, Hyonchol Woo, Sang Myung Park, Jong Bae Lee, Seon-Hyeong Kang, Joon Hee Kim, Hee Yeon Song, Jaewhan Kim, Soo-Youl Cells Article The greatest challenge in cancer therapy is posed by drug-resistant recurrence following treatment. Anticancer chemotherapy is largely focused on targeting the rapid proliferation and biosynthesis of cancer cells. This strategy has the potential to trigger autophagy, enabling cancer cell survival through the recycling of molecules and energy essential for biosynthesis, leading to drug resistance. Autophagy recycling contributes amino acids and ATP to restore mTOR complex 1 (mTORC1) activity, which leads to cell survival. However, autophagy with mTORC1 activation can be stalled by reducing the ATP level. We have previously shown that cytosolic NADH production supported by aldehyde dehydrogenase (ALDH) is critical for supplying ATP through oxidative phosphorylation (OxPhos) in cancer cell mitochondria. Inhibitors of the mitochondrial complex I of the OxPhos electron transfer chain and ALDH significantly reduce the ATP level selectively in cancer cells, terminating autophagy triggered by anticancer drug treatment. With the aim of overcoming drug resistance, we investigated combining the inhibition of mitochondrial complex I, using phenformin, and ALDH, using gossypol, with anticancer drug treatment. Here, we show that OxPhos targeting combined with anticancer drugs acts synergistically to enhance the anticancer effect in mouse xenograft models of various cancers, which suggests a potential therapeutic approach for drug-resistant cancer. MDPI 2020-09-01 /pmc/articles/PMC7565066/ /pubmed/32883024 http://dx.doi.org/10.3390/cells9092013 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Jae-Seon
Lee, Ho
Jang, Hyonchol
Woo, Sang Myung
Park, Jong Bae
Lee, Seon-Hyeong
Kang, Joon Hee
Kim, Hee Yeon
Song, Jaewhan
Kim, Soo-Youl
Targeting Oxidative Phosphorylation Reverses Drug Resistance in Cancer Cells by Blocking Autophagy Recycling
title Targeting Oxidative Phosphorylation Reverses Drug Resistance in Cancer Cells by Blocking Autophagy Recycling
title_full Targeting Oxidative Phosphorylation Reverses Drug Resistance in Cancer Cells by Blocking Autophagy Recycling
title_fullStr Targeting Oxidative Phosphorylation Reverses Drug Resistance in Cancer Cells by Blocking Autophagy Recycling
title_full_unstemmed Targeting Oxidative Phosphorylation Reverses Drug Resistance in Cancer Cells by Blocking Autophagy Recycling
title_short Targeting Oxidative Phosphorylation Reverses Drug Resistance in Cancer Cells by Blocking Autophagy Recycling
title_sort targeting oxidative phosphorylation reverses drug resistance in cancer cells by blocking autophagy recycling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565066/
https://www.ncbi.nlm.nih.gov/pubmed/32883024
http://dx.doi.org/10.3390/cells9092013
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