Lipoic Acid Synergizes with Antineoplastic Drugs in Colorectal Cancer by Targeting p53 for Proteasomal Degradation.

Carina Neitzel,Carina Weber,Svenja Stroh,Birgit Rasenberger,Markus Christmann,Jörg Fahrer,Erika Diehl,Georg Nagel,Nina Seiwert,Anja Göder

doi:10.3390/cells8080794

Abstract

Lipoic acid (LA) is a redox-active disulphide compound, which functions as a pivotal co-factor for mitochondrial oxidative decarboxylation. LA and chemical derivatives were shown to target mitochondria in cancer cells with altered energy metabolism, thereby inducing cell death. In this study, the impact of LA on the tumor suppressor protein p53 was analyzed in various colorectal cancer (CRC) cell lines, with a focus on the mechanisms driving p53 degradation. First, LA was demonstrated to trigger the depletion of both wildtype and mutant p53 protein in all CRC cells tested without influencing its gene expression and preceded LA-triggered cytotoxicity. Depletion of p53 coincided with a moderate, LA-dependent ROS production, but was not rescued by antioxidant treatment. LA induced the autophagy receptor p62 and differentially modulated autophagosome formation in CRC cells. However, p53 degradation was not mediated via autophagy as shown by chemical inhibition and genetic abrogation of autophagy. LA treatment also stabilized and activated the transcription factor Nrf2 in CRC cells, which was however dispensable for p53 degradation. Mechanistically, p53 was found to be readily ubiquitinylated and degraded by the proteasomal machinery following LA treatment, which did not involve the E3 ubiquitin ligase MDM2. Intriguingly, the combination of LA and anticancer drugs (doxorubicin, 5-fluorouracil) attenuated p53-mediated stabilization of p21 and resulted in synergistic killing in CRC cells in a p53-dependant manner.

Highlights

The natural compound α-lipoic acid (LA) is a chiral fatty acid harboring a disulphide bond, which can be reduced to dihydrolipoic acid (DHLA) [1]
LA Leads to the Depletion of Wildtype and Mutant p53 in colorectal cancer (CRC) Cell Lines
We provided evidence that cell death induction by LA in CRC cells is independent of p53 and was not accompanied by initial p53 stabilization [15]

Summary

Introduction

The natural compound α-lipoic acid (LA) is a chiral fatty acid harboring a disulphide bond, which can be reduced to dihydrolipoic acid (DHLA) [1]. The biologically active (R)-enantiomer represents an essential co-factor in mitochondrial multi-enzyme complexes performing oxidative decarboxylation (alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase). It represents a crucial player in the citric acid cycle and aerobic metabolism. LA and DHLA form a potent redox couple displaying remarkable anti-oxidative properties—e.g., by chelating divalent metal ions and by regenerating vitamin C [2,3,4]. LA was further shown to act anti-inflammatory by downregulating the pro-inflammatory NF-κB pathway [3]. LA is available as food supplement, Cells 2019, 8, 794; doi:10.3390/cells8080794 www.mdpi.com/journal/cells

Objectives

Methods

Results

Discussion

Conclusion