Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1

Area of Science:

• Hepatocellular Carcinoma Research
• Cancer Cell Signaling
• Metabolic Pathways in Oncology

Background:

• Sorafenib is a key treatment for advanced hepatocellular carcinoma (HCC).
• Acquired resistance to sorafenib is a significant clinical challenge.
• The nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin 1 (SIRT1) pathway is implicated in sorafenib resistance.

Purpose of the Study:

• To investigate the influence of cellular NAD levels and SIRT1 function on sorafenib efficacy in HCC.
• To analyze the effects of sorafenib on apoptosis, NAD metabolism, mitochondrial function, and related signaling pathways.
• To determine if SIRT1 overexpression or NAD repletion affects sorafenib response.

Main Methods:

• Utilized HCC cell lines (HepG2, Hep3B, HUH7) with manipulated SIRT1 levels or NAD supplementation (NMN).
• Assessed sorafenib's impact on apoptosis, NAD concentrations, mitochondrial respiration, citrate synthase activity, and ATP levels.
• Monitored signaling pathways including AMPK and mTOR.

Main Results:

• Sorafenib induced apoptosis and decreased cellular NAD concentrations in HCC cells.
• Mitochondrial function (respiration, ATP production) and citrate synthase activity were reduced post-sorafenib treatment.
• SIRT1 overexpression or NMN supplementation attenuated sorafenib-induced apoptosis, suggesting a role in resistance.
• Sorafenib treatment activated AMPK and inhibited mTOR, indicating energy deprivation.

Conclusions:

• Sorafenib treatment modulates the NAD/SIRT1/AMPK signaling axis.
• Cellular NAD levels and SIRT1 activity are critical determinants of sorafenib response in HCC.
• SIRT1 overexpression may represent a mechanism of resistance to sorafenib in hepatocellular carcinoma.