Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1.

Abstract

Sorafenib is a multi-kinase inhibitor and one of the few systemic treatment options for patients with advanced hepatocellular carcinomas (HCCs). Resistance to sorafenib develops frequently and could be mediated by the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin (SIRT)1. We aimed to test whether sorafenib efficacy is influenced by cellular NAD levels and NAD-dependent SIRT1 function. We analyzed sorafenib effects on apoptosis induction, NAD salvage, mitochondrial function, and related signaling pathways in HCC cell lines (HepG2, Hep3B, und HUH7) overexpressing SIRT1 or supplemented with the NAD metabolite nicotinamide mononucleotide (NMN) compared to controls. Treatment of HCC cell lines with sorafenib dose-dependently induced apoptosis and a significant decrease in cellular NAD concentrations. The SIRT1 protein was downregulated in HUH7 cells but not in Hep3B cells. After sorafenib treatment, mitochondrial respiration in permeabilized cells was lower, citrate synthase activity was attenuated, and cellular adenosine triphosphate (ATP) levels were decreased. Concomitant to increased phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), sorafenib treatment led to decreased activity of the mechanistic target of rapamycin (mTOR), indicative of energy deprivation. Transient overexpression of SIRT1, as well as NAD repletion by NMN, decreased sorafenib-induced apoptosis. We can, therefore, conclude that sorafenib influences the NAD/SIRT1/AMPK axis. Overexpression of SIRT1 could be an underlying mechanism of resistance to sorafenib treatment in HCC.

• Authors: Antje Garten, Theresa Grohmann, Katarina Kluckova, Gareth G Lavery, Wieland Kiess, Melanie Penke
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 20 Issue 16 (Aug 19 2019) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 31430957 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Nicotinamide Mononucleotide
• Sorafenib
• SIRT1 protein, human
• Sirtuin 1

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, metabolism)
• Cell Line, Tumor
• Humans
• Liver Neoplasms (drug therapy, metabolism)
• Nicotinamide Mononucleotide (metabolism)
• Sirtuin 1 (metabolism)
• Sorafenib (pharmacology)