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

Jae Seon Lee, Ho Lee, Hyonchol Jang, Sang Myung Woo, Jong Bae Park, Seon Hyeong Lee, Joon Hee Kang, Hee Yeon Kim, Jaewhan Song, Soo Youl Kim

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalCells
Volume9
Issue number9
DOIs
Publication statusPublished - 2020 Sep 1

Bibliographical note

Funding Information:
This work was supported by the Postdoctoral Research Funding of Guangzhou Women and Children?s Medical Center (5001-3001021), China Postdoctoral Science Foundation (NO.2015M582368), National Natural Science Foundation of China (81301758), we also gratefully thank the National Natural Science Foundation of Hainan Province (NO.20168290 & NO.15A200083) for financial support of this work.

Funding Information:
Acknowledgements. This work was supported by the Postdoctoral Research Funding of Guangzhou Women and Children’s Medical Center (5001-3001021), China Postdoctoral Science Foundation (NO.2015M582368), National Natural Science Foundation of China (81301758), we also gratefully thank the National Natural Science Foundation of Hainan Province (NO.20168290 & NO.15A200083) for financial support of this work.

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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