Suppression of NASH-Related HCC by Farnesyltransferase Inhibitor through Inhibition of Inflammation and Hypoxia-Inducible Factor-1α Expression

Abstract

Inflammatory processes play major roles in carcinogenesis and the progression of hepatocellular carcinoma (HCC) derived from non-alcoholic steatohepatitis (NASH). But, there are no therapies for NASH-related HCC, especially focusing on these critical steps. Previous studies have reported that farnesyltransferase inhibitors (FTIs) have anti-inflammatory and anti-tumor effects. However, the influence of FTIs on NASH-related HCC has not been elucidated. In hepatoblastoma and HCC cell lines, HepG2, Hep3B, and Huh-7, we confirmed the expression of hypoxia-inducible factor (HIF)-1α, an accelerator of tumor aggressiveness and the inflammatory response. We established NASH-related HCC models under inflammation and free fatty acid burden and confirmed that HIF-1α expression was increased under both conditions. Tipifarnib, which is an FTI, strongly suppressed increased HIF-1α, inhibited cell proliferation, and induced apoptosis. Simultaneously, intracellular interleukin-6 as an inflammation marker was increased under both conditions and significantly suppressed by tipifarnib. Additionally, tipifarnib suppressed the expression of phosphorylated nuclear factor-κB and transforming growth factor-β. Finally, in a NASH-related HCC mouse model burdened with diethylnitrosamine and a high-fat diet, tipifarnib significantly reduced tumor nodule formation in association with decreased serum interleukin-6. In conclusion, tipifarnib has anti-tumor and anti-inflammatory effects in a NASH-related HCC model and may be a promising new agent to treat this disease.

Crosstalk between Epigenetics and Metabolic Reprogramming in Metabolic Dysfunction-Associated Steatotic Liver Disease-Induced Hepatocellular Carcinoma: A New Sight

“…Patients with MASLD-induced HCC have been found to exhibit activation of the mTOR pathway, increased lipid accumulation, and upregulated hypoxia-inducible transcription factor (HIF)-2α [ 113 ]. Consequently, the activation of HIF-1α combined with the secretion of inflammatory cytokines could drive metabolic reprogramming, promote the growth of new blood vessels, and stimulate cell proliferation, ultimately facilitating the transition from MASH to HCC [ 114 ]. Fujinuma and colleagues demonstrated that the forkhead box K1 (FOXK1) protein inhibits the process of hepatic FAO in a manner dependent on mTORC1.…”

The Role of CD4+T Cells in Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

“…Tipifarnib, an arnesyltransferase inhibitor, strongly suppressed HIF-1α upregulation and inhibited cancer cell proliferation while concurrently inducing cancer cell apoptosis, possibly via upregulation of ROS production. Moreover, in the NASH-driven HCC mouse model induced by a diethylnitrosamine (DEN) + choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), treatment with tipifarnib significantly ameliorated tumor nodule formation in association with decreased serum interleukin-6 levels [113].…”