Gamma-tocotrienol Inhibits Proliferation and Growth of HSD17B4 Overexpressing HepG2 Liver Cancer Cells

Introduction Hydroxysteroid 17-beta dehydrogenase 4 (HSD17B4) is involved in the progression of hepatocellular carcinoma (HCC).Aims This study aimed to investigate the inhibitory effect of gamma-tocotrienol (gamma-T3) on the proliferation and growth of HSD17B4-overexpressing HepG2 cells.Methods HepG2 cells were transfected with empty or HSD17B4-overexpressing plasmids, followed by vitamin E (VE) or gamma-T3 treatment. MTS assay, Western blotting, qRT-PCR, and flow cytometry were employed to assess cell proliferation, protein expression, mRNA levels, and apoptosis. HSD17B4 interaction with gamma-T3 was assessed by quantifying gamma-T3 in the collected precipitate of HSD17B4 using anti-flag magnetic beads. Tumor xenografts were established in NSG mice, and tumor growth was monitored.Results HSD17B4 overexpression significantly promoted HepG2 cell proliferation, which was effectively counteracted by VE or gamma-T3 treatment in a dose-dependent manner. VE and gamma-T3 did not exert their effects through direct regulation of HSD17B4 expression. Instead, gamma-T3 was found to interact with HSD17B4, inhibiting its activity in catalyzing the conversion of estradiol (E2) into estrone. Moreover, gamma-T3 treatment led to a reduction in cyclin D1 expression and suppressed key proliferation signaling pathways, such as ERK, MEK, AKT, and STAT3. Additionally, gamma-T3 promoted apoptosis in HSD17B4-overexpressing HepG2 cells. In an in vivo model, gamma-T3 effectively reduced the growth of HepG2 xenograft tumors.Conclusion In conclusion, our study demonstrates that gamma-T3 exhibits potent anti-proliferative and anti-tumor effects against HepG2 cells overexpressing HSD17B4. These findings highlight the therapeutic potential of gamma-T3 in HCC treatment and suggest its role in targeting HSD17B4-associated pathways to inhibit tumor growth and enhance apoptosis.