Columbamine suppresses hepatocellular carcinoma cells through down-regulation of PI3K/AKT, p38 and ERK1/2 MAPK signaling pathways

Abstract

Hepatocellular carcinoma (HCC) as primary liver cancer in adults is the most common cause led to internal cirrhosis responsible for patients' death, which resulted in nearly a million deaths worldwide on both males and females in the developing and developed countries. Unfortunately, up to date, there are no highly effective treatment of medicine on HCC as lack of comprehensive cellular and molecular mechanism. According to the sources of human ancient history of medicine, traditional medicine could provide unique treatment to discontinue the challenging HCC. In this study, we inspected the effect of Columbamine (Col; C20H21NO5), an alkaloid isolated from calumba, on HCC utilizing three HCC cell-lines i.e. SMMC7721, HepG2 and Hep3B. Our data collected from these cell-lines exhibit strong Col suppression on the cell growth accompanying the dosage-dependent suppression, and we further confirmed the suppression on the tumor-growth in animal model. Rational of the Col suppression presents cellular mechanism by limiting the proliferation and colony formation of the cells marked with decreased expression of PCNA. Meanwhile decreases of migration indicated with increasing expression of E-cadherin and decreasing expression of N-cadherin, and of invasion labelled with decreasing expressions of MMP2 and MMP9, are accompanying the Col suppression along with the Col promoted apoptosis of the tumor cells. This programmed cell death marketed with cleaved Caspase 3 plus PAPR proteins, up-regulation of BAD and down-regulation of BCL2 is linked the Col suppression to unique calcium-related pathways. Our results unveiled that the Columbamine suppression on HCC based on the traditional medicine are clearly associated with PI3K/AKT, p38 and ERK1/2 MAPKs signaling pathways and guide further research orientation for developing the Col medicine against hepatocellular carcinoma.