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

• Published in: Cells (Basel, Switzerland) Vol. 9; no. 9; p. 2013
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.09.2020; MDPI
• Subjects: Adenosine triphosphate; Aldehyde dehydrogenase; Aldehyde Dehydrogenase - antagonists & inhibitors; Animal models; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor agents; Apoptosis; ATP production; Autophagy; Autophagy (Cytology); Autophagy - drug effects; Biosynthesis; Cancer; Cancer cells; cancer metabolism; Cancer therapies; Cell proliferation; Cell survival; Chemotherapy; Cytotoxicity; Deoxyribonucleic acid; DNA; Drug delivery; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Electron transfer; Electron transport chain; Electron Transport Complex I - antagonists & inhibitors; energy metabolism; Gastric cancer; Gossypol; Gossypol - pharmacology; Gossypol - therapeutic use; Health aspects; HT29 Cells; Humans; Melanoma; Mice; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; NADH; NADH-ubiquinone oxidoreductase; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Oxidative phosphorylation; oxidative phosphorylation (OxPhos); Oxidative Phosphorylation - drug effects; Pancreatic cancer; Phagocytosis; Phenformin - pharmacology; Phenformin - therapeutic use; Phosphorylation; Prevention; Proteins; TOR protein; Xenograft Model Antitumor Assays; Xenografts; South Korea; United States > US; cancer metabolism; ATP production; oxidative phosphorylation (OxPhos); aldehyde dehydrogenase; energy metabolism
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells9092013

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.