Abstract
Autophagy targets cellular components for lysosomal-dependent degradation in which the products of degradation may be recycled for protein synthesis and utilized for energy production. Autophagy also plays a critical role in cell homeostasis and the regulation of many physiological and pathological processes and prompts this investigation of new agents to effect abnormal autophagy in hepatocellular carcinoma (HCC). 2,5-Dichloro-N-(2-methyl-4-nitrophenyl) benzenesulfonamide (FH535) is a synthetic inhibitor of the Wnt/β-catenin pathway that exhibits anti-proliferative and anti-angiogenic effects on different types of cancer cells. The combination of FH535 with sorafenib promotes a synergistic inhibition of HCC and liver cancer stem cell proliferation, mediated in part by the simultaneous disruption of mitochondrial respiration and glycolysis. We demonstrated that FH535 decreased HCC tumor progression in a mouse xenograft model. For the first time, we showed the inhibitory effect of an FH535 derivative, FH535-N, alone and in combination with sorafenib on HCC cell proliferation. Our study revealed the contributing effect of Wnt/β-catenin pathway inhibition by FH535 and its derivative (FH535-N) through disruption of the autophagic flux in HCC cells.
Highlights
Hepatocellular carcinoma (HCC) is the most prevalent, primary malignancy of the liver and one of the leading causes of cancer-related deaths
We investigate the effect of FH535 on HCC tumor progression in a mouse xenograft model and explore the underlying mechanism of FH535 and its derivatives in modulating the Wnt/β-catenin-dependent autophagic flux in HCC
When HCC tumors reached a volume of 100 mm3, mice were injected with DMSO vehicle or 15 mg/kg of FH535 every other day
Summary
Hepatocellular carcinoma (HCC) is the most prevalent, primary malignancy of the liver and one of the leading causes of cancer-related deaths. Current statistics indicate this cancer affects over 700,000 people worldwide and causes an estimated 600,000 deaths annually [1, 2]. Autophagy and β-catenin modulation in HCC study design, data collection and analysis, decision to publish, or preparation of the manuscript
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