Abstract
BackgroundHepatocellular carcinoma (HCC) is the seventh most common malignancy and the third leading cause of cancer-related death worldwide with an extremely grim prognosis. Berberine (BBR) has been found to inhibit proliferation of human HCC cells, although the underlying mechanism(s) are unclear.MethodsProtein expression was detected by Western blots. Cell viability was determined by using the CellTiter Assay kit.ResultsWe confirm that BBR treatment inhibits HepG2, Hep3B, and SNU-182 cell viability, and suggest that it regulates this proliferation via the modulation of multiple tumorigenesis-related genes protein expression. BBR treatment up-regulated protein expression of tumor suppressor genes, including Kruppel-like factor 6 (KLF6), activating transcription factor 3 (ATF3) and p21, while down-regulating the expression of selected oncogenes, including E2F transcription factor 1 (E2F1) and pituitary tumor transforming gene 1 (PTTG1). The specific extracellular signal–regulated kinases 1/2 (ERK1/2) inhibitor, PD98059, partially inhibited BBR effects including reduction of cell viability, and up-regulation of KLF6 and ATF3 expressions; although, PD98059 did not alter the down-regulation of E2F1 and PTTG1 expression by BBR.ConclusionsOur results suggest that BBR inhibits HCC cell viability by modulating multiple tumorigenesis-related genes, and that up-regulation of tumor suppressor genes by BBR is in part the result of ERK1/2 action. The results of this study augment our understanding of the mechanisms underlying the effect of BBR on hepatocellular cancers and provide further evidence as to the biological plausibility of this agent’s role in the treatment of these malignancies.
Highlights
Hepatocellular carcinoma (HCC) is the seventh most common malignancy and the third leading cause of cancer-related death worldwide with an extremely grim prognosis
BBR inhibits HCC cells viability in a time and dose‐dependent manner Three HCC cell lines were treated with BBR in concentrations of 0, 10, 20, 50 and 100 μM for 24 and 72 h
As HepG2 expresses wild type p53 and Hep3B is a p53-deficient HCC cell line, these results suggest that BBR regulation of Kruppel-like factor 6 (KLF6), p21 and pituitary tumor transforming gene 1 (PTTG1) expression is possibly p53 dependent
Summary
Hepatocellular carcinoma (HCC) is the seventh most common malignancy and the third leading cause of cancer-related death worldwide with an extremely grim prognosis. Berberine (BBR) has been found to inhibit prolif‐ eration of human HCC cells, the underlying mechanism(s) are unclear. Hepatocellular carcinoma (HCC) is the seventh most common cancer and the third leading cause of cancer death worldwide, with few therapeutic options [1]. In HCC, BBR inhibits proliferation and migration as well as induces cell cycle arrest and apoptosis [8, 14,15,16,17,18,19]. BBR demonstrates very low to no cytotoxic effect on healthy liver tissue [18]. BBR appears to have a protective effect on healthy liver tissue protective against chemicallyinduced hepatotoxicity [20]
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