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

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

doi:10.3390/cells9092013

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.

Highlights

Resistance to chemotherapeutic drugs is a leading cause of death from cancer and, a major focus in cancer research
We found that wild-type cancer cells die via apoptosis and necrosis, while drug-resistant cells survive through autophagy accompanied by mTOR activation. mTOR can be activated by growth factors and nutrients such as amino acids and adenosine triphosphate (ATP) [27]
We observed that anticancer drug treatment triggers autophagy, which requires more ATP through the activation of oxidative phosphorylation (OxPhos) for cancer cell survival

Summary

Introduction

Resistance to chemotherapeutic drugs is a leading cause of death from cancer and, a major focus in cancer research. Many mechanisms of drug resistance have been proposed based on the expression of a unique set of genes that dictate tumor progression under chemotherapy [1,2]. Targeting the signaling pathways of the genes and enzymes associated with biosynthesis is unlikely to lead to a method to overcome drug resistance in cancer because such therapeutics can elicit various rerouting pathways in tumor cells [3,4]. Autophagy enhancement in response to chemotherapy has been considered as a major mechanism of drug resistance [5]. Autophagy is suggested as a therapeutic target for overcoming anticancer drug resistance, how the level of autophagy could be changed to achieve this remains under investigation [8,9]

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Conclusion