Mitochondrial metabolic study guided by proteomics analysis in hepatocellular carcinoma cells surviving long-term incubation with the highest dose of sorafenib

Abstract

Sorafenib is the standard first-line systemic therapy for hepatocellular carcinoma (HCC). However, the low objective response rates in clinical studies suggest the existence of certain HCC cells that are inherently insensitive to sorafenib. To understand the molecular basis of insensitivity of HCC cells to sorafenib, this study developed 3 kinds of insensitive HCC cells through exposure to various concentrations of sorafenib and performed a quantitative proteome analysis of the surviving HepG2 cells. 520 unique proteins were concentration-dependently upregulated by sorafenib. Bioinformatics-assisted analysis of 520 proteins revealed that the metabolic pathways involved in central carbon metabolism were significantly enriched, and 102 mitochondrial proteins, especially components of the electron transport chain (ETC), were incrementally upregulated in the 3 kinds of insensitive cells. Conversely, we identified a rapid holistic inhibitory effect of sorafenib on mitochondrial function by the direct targeting of the complex I-linked electron transport and the uncoupling of mitochondrial oxidative phosphorylation (OXHPOS) in HCC cells. Core metabolic reprogramming involved in a compensatory upregulation of OXHPOS combined with elevated glycolysis supports the survival of HCC cells under the highest dose of sorafenib treatment. Altogether, our work thus elaborates an ETC inhibitor and unveils the proteomic landscape of metabolic reprogramming in drug insensitivity.

Fasting reverses drug-resistance in hepatocellular carcinoma through p53-dependent metabolic synergism

“…Several previous studies have described the impact of sorafenib on mitochondrial bioenergetics [39,48–50]. Furthermore, AKT activation boosts aerobic glycolysis in cancer cells with defective mitochondria [51].…”

Identifying Potential Mitochondrial Proteome Signatures Associated with the Pathogenesis of Pulmonary Arterial Hypertension in the Rat Model

“…Mitochondrial proteomics provides essential data for studying mitochondrial dysfunction, disease diagnostic markers, and finding target drugs. The mitochondrial proteome study can intuitively see the mitochondrial protein changes after therapy in some diseases [15][16][17]. Highthroughput LC-MS/MS technologies have developed significantly over the last ten years.…”

Sorafenib and nitazoxanide disrupt mitochondrial function and inhibit regrowth capacity in three-dimensional models of hepatocellular and colorectal carcinoma

“…It seems reasonable to assume that increasing hypoxia and nutritional restriction will enhance tumor sensitivity to OXPHOS inhibition. Resistance to sorafenib is associated with increased OXPHOS-capacity, further emphasizing the importance of mitochondrial uncoupling in the mechanism of action of sorafenib 49 . Sorafenib and regorafenib both have dose-limiting side effects.…”