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
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:89543 |
| Date | 06 February 2024 |
| Creators | Garten, Antje, Grohmann, Theresa, Klockova, Katarina, Lavery, Gareth G., Kiess, Wieland, Penke, Melanie |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 4048 |
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