Yamada, K.; Tanaka, T.; Kai, K.; Matsufuji, S.; Ito, K.; Kitajima, Y.; Manabe, T.; Noshiro, H. Suppression of NASH-Related HCC by Farnesyltransferase Inhibitor through Inhibition of Inflammation and Hypoxia-Inducible Factor-1α Expression. Int. J. Mol. Sci.2023, 24, 11546.
Yamada, K.; Tanaka, T.; Kai, K.; Matsufuji, S.; Ito, K.; Kitajima, Y.; Manabe, T.; Noshiro, H. Suppression of NASH-Related HCC by Farnesyltransferase Inhibitor through Inhibition of Inflammation and Hypoxia-Inducible Factor-1α Expression. Int. J. Mol. Sci. 2023, 24, 11546.
Yamada, K.; Tanaka, T.; Kai, K.; Matsufuji, S.; Ito, K.; Kitajima, Y.; Manabe, T.; Noshiro, H. Suppression of NASH-Related HCC by Farnesyltransferase Inhibitor through Inhibition of Inflammation and Hypoxia-Inducible Factor-1α Expression. Int. J. Mol. Sci.2023, 24, 11546.
Yamada, K.; Tanaka, T.; Kai, K.; Matsufuji, S.; Ito, K.; Kitajima, Y.; Manabe, T.; Noshiro, H. Suppression of NASH-Related HCC by Farnesyltransferase Inhibitor through Inhibition of Inflammation and Hypoxia-Inducible Factor-1α Expression. Int. J. Mol. Sci. 2023, 24, 11546.
Abstract
Inflammatory processes play major roles in carcinogenesis and 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 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 HCC cell lines, HepG2, Hep3B, and Huh-7, we confirmed 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 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.
Medicine and Pharmacology, Gastroenterology and Hepatology
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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