Pyruvate Dehydrogenase Contributes to Drug Resistance of Lung Cancer Cells Through Epithelial Mesenchymal Transition.

Buse Cevatemre,Engin Ulukaya,Sukru Dilege,Ceyda Acilan,Egemen Dere

doi:10.3389/fcell.2021.738916

Abstract

Recently, there has been a growing interest on the role of mitochondria in metastatic cascade. Several reports have shown the preferential utilization of glycolytic pathway instead of mitochondrial respiration for energy production and the pyruvate dehydrogenase (PDH) has been considered to be a contributor to this switch in some cancers. Since epithelial mesenchymal transition (EMT) is proposed to be one of the significant mediators of metastasis, the molecular connections between cancer cell metabolism and EMT may reveal underlying mechanisms and improve our understanding on metastasis. In order to explore a potential role for PDH inhibition on EMT and associated drug resistance, we took both pharmacological and genetic approaches, and selectively inhibited or knocked down PDHA1 by using Cpi613 and shPDHA1, respectively. We found that both approaches triggered morphological changes and characteristics of EMT (increase in mesenchymal markers). This change was accompanied by enhanced wound healing and an increase in migration. Interestingly, cells were more resistant to many of the clinically used chemotherapeutics following PDH inhibition or PDHA1 knockdown. Furthermore, the TGFβRI (known as a major inducer of the EMT) inhibitor (SB-431542) together with the PDHi, was effective in reversing EMT. In conclusion, interfering with PDH induced EMT, and more importantly resulted in chemoresistance. Therefore, our study demonstrates the need for careful consideration of PDH-targeting approaches in cancer treatment.

Highlights

The survival and growth of cancer cells usually involve changes in the metabolic pathways and reprogramming, in various cancer types, dysregulated metabolism is considered as an important hallmark (Hanahan and Weinberg, 2011)
In order to examine the effect of PDHi (Cpi613/Devimistat) on cancer cell growth, its cytotoxicity was evaluated on a number of cells of different origins such as lung (A549), breast (MCF7) and colorectal (HT29) cancers
The goal of this study was to investigate whether pyruvate dehydrogenase (PDH), the gate-keeper of mitochondria, is involved in epithelial mesenchymal transition (EMT)

Summary

Introduction

The survival and growth of cancer cells usually involve changes in the metabolic pathways and reprogramming, in various cancer types, dysregulated metabolism is considered as an important hallmark (Hanahan and Weinberg, 2011). The pyruvate dehydrogenase (PDH), the gatekeeper enzyme in glucose metabolism, produces acetyl-CoA by oxidatively decarboxylating pyruvate to fuel mitochondrial tricarboxylic acid cycle (TCA). It plays a critical role in the metabolic axis by separating pyruvate between glycolysis and the TCA. Knockout of PDHA1 resulted in higher stemness phenotype in prostate cancer (Zhong et al, 2017) and led to Warburg effect with aggressive traits in esophageal squamous cancer in vitro and in vivo (Liu et al, 2019)

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