Alpha lipoic acid diminishes migration and invasion in hepatocellular carcinoma cells through an AMPK-p53 axis

Abstract

Abstract Hepatocellular carcinoma (HCC) associated with viral or metabolic liver diseases is a growing cancer that lacks effective therapy. AMPK is downregulated in the early stages of HCC and its activation diminishes tumor progression in culture and in vivo. Alpha lipoic acid (ALA), an indirect AMPK activator that inhibits hepatic steatosis in rodents, shows antitumor effects in different cancers. We aimed to study the putative antitumor action of ALA in HCC cells through AMPK signaling. ALA led to significant inhibition of cell migration and invasion in HCC cells with wild-type TP53. We showed that these effects depended on AMPK, and ALA also increased the levels and nuclear compartmentalization of the AMPK target p53. The anti-invasive effect of ALA was abrogated in stable-silenced versus isogenic-TP53 cells. Furthermore, ALA inhibited epithelial-mesenchymal transition in control wild-type TP53, but no significant changes of EMT markers were observed in silenced TP53 cells. In addition, we spotted that in patients from the HCC-TCGA dataset some EMT genes showed different expression patterns or survival profiles depending on TP53 status. ALA emerges as a potent activator of AMPK-p53 axis in HCC cells, and it decreases migration/invasion by reducing EMT which could mitigate the disease in wild-type TP53 patients.