α-Lipoic Acid Targeting PDK1/NRF2 Axis Contributes to the Apoptosis Effect of Lung Cancer Cells.

Liduo Yue,Xiangyun Chen,Kai Wang,Lihong Fan,Tiansheng Zheng,Guojie Chen,Yanbei Ren,Qingxi Yue,Zhou Ding,Ming Li,Luciana Hannibal

doi:10.1155/2021/6633419

Abstract

As an antioxidant, α-lipoic acid (LA) has attracted much attention to cancer research. However, the exact mechanism of LA in cancer progression control and prevention remains to be unclear. In this study, we demonstrated that α-lipoic acid has inhibitory effects on the proliferation, migration, and proapoptotic effects of non-small-cell lung cancer (NSCLC) cell lines A549 and PC9. LA-induced NSCLC cell apoptosis was mediated by elevated mitochondrial reactive oxygen species (ROS). Further study confirmed that it is by downregulating the expression of PDK1 (the PDH kinase), resulted in less phospho-PDH phenotype which could interact with Keap1, the negative controller of NRF2, directly leading to NRF2 decrease. Thus, by downregulating the NRF2 antioxidant system, LA plays a role in promoting apoptosis through the ROS signaling pathway. Moreover, LA could enhance other PDK inhibitors with the proapoptosis effect. In summary, our study shows that LA promotes apoptosis and exerts its antitumor activity against lung cancer by regulating mitochondrial energy metabolism enzyme-related antioxidative stress system. Administration of LA to the tumor-bearing animal model further supported the antitumor effect of LA. These findings provided new ideas for the clinical application of LA in the field of cancer therapy.

Highlights

Cancer cells exhibit increased reactive oxygen species (ROS) levels, partly due to oncogenic stimulation compared to normal cells, increasing their metabolic activity [1,2,3]
We demonstrated that inducing degradation of nuclear factor erythroid 2-related factor 2 (NRF2) by inhibiting PDK1 is a promising strategy to combat lung cancer
With the progression of cancer development, ROS rises with redox press

Summary

Introduction

Cancer cells exhibit increased ROS levels, partly due to oncogenic stimulation compared to normal cells, increasing their metabolic activity [1,2,3]. The cancer cells could upregulate nuclear factor erythroid 2-related factor 2 (NRF2), the antioxidant system to inhibit the apoptotic pathway [5]. Cancer cells become well adapted to such stress through a set of mechanisms that activate ROS-scavenging systems, including NRF2-Keap1-ARE system, and inhibit apoptosis [6]. The NRF2 is highly expressed, antioxidant proteins are upregulated, and the cells escape from apoptosis. PDH complex catalyzes the oxidative decarboxylation of α-keto acids, such as pyruvate and α-ketoglutarate [16] It regulates various metabolic enzymes in glucose catabolism [17]. We test if LA could influence the metabolic feature and directly regulate the antioxidant system to promote apoptosis on these two cell lines

Result

Discussion

Material and Methods