Berberine induces caspase-independent cell death in colon tumor cells through activation of apoptosis-inducing factor

Keith Wilson,Rupesh Chaturvedi,D Brent Polk,Hamwei Cao,Fang Yan,Yan Shi,Liping Liu,Tianhui Hu,Lihong Wang

doi:10.1038/npre.2011.6438.1

Abstract

AbstractBerberine, an isoquinoline alkaloid derived from plants, is a traditional medicine for treating bacterial diarrhea and intestinal parasite infections. Although berberine has recently been shown to suppress growth of several tumor cell lines, information regarding the effect of berberine on colon tumor growth is limited. Here, we investigated the mechanisms underlying the effects of berberine on regulating the fate of colon tumor cells, specifically the immorto Min mouse colonic epithelial (IMCE) cells carrying the Apcmin mutation, and of normal colon epithelial cells, namely young adult mouse colon (YAMC) epithelial cells. Berberine decreased colon tumor colony formation in agar, and induced cell death and LDH release in a time- and concentration-dependent manner in IMCE cells. In contrast, YAMC cells were not sensitive to berberine-induced cell death. Berberine did not stimulate caspase activation, and PARP cleavage and berberine-induced cell death were not affected by a caspase inhibitor in IMCE cells. Rather, berberine stimulated a caspase-independent cell death mediator, apoptosis-inducing factor (AIF) release from mitochondria and nuclear translocation in a ROS production-dependent manner. Amelioration of berberine-stimulated ROS production or suppression of AIF expression blocked berberine-induced cell death and LDH release in IMCE cells. Furthermore, two targets of ROS production in cells, cathepsin B release from lysosomes and PARP activation were induced by berberine. Blockage of either of these pathways decreased berberine-induced AIF activation and cell death in IMCE cells. Thus, berberine-stimulated ROS production leads to cathepsin B release and PARP activation-dependent AIF activation, resulting in caspase-independent cell death in colon tumor cells. Notably, normal colon epithelial cells are less susceptible to berberine-induced cell death, which suggests the specific inhibitory effects of berberine on colon tumor cell growth.

Highlights

IntroductionBerberine is an isoquinoline alkaloid isolated from several plants, such as Hydrastis canadensis (goldenseal), Berberis aquifolium (oregon grape), and Berberis vulgaris (barberry)
Berberine is an isoquinoline alkaloid isolated from several plants, such as Hydrastis canadensis, Berberis aquifolium, and Berberis vulgaris
We used immorto-multiple intestinal neoplasia (Min) mouse colon epithelium (IMCE) cells isolated from the colonic epithelium of the Apcmin/+ mouse crossed with the Immortomouse as a colon cancer cell model

Summary

Introduction

Berberine is an isoquinoline alkaloid isolated from several plants, such as Hydrastis canadensis (goldenseal), Berberis aquifolium (oregon grape), and Berberis vulgaris (barberry). Other effects of berberine on diseases include reducing cholesterol levels in humans and hamsters by elevating LDL receptor expression (Kong et al 2004), inhibiting hepatic gluconeogenesis to improve glucose metabolism in diabetic rats (Xia et al 2011), and reducing the permeability of the blood-brain barrier and attenuating autoimmune encephalomyelitis in mice (Ma et al 2010). Signaling pathways involved in anti-cancer effects of berberine include p53, MAPK, and NF-κB (Reviewed in (Sun et al 2009, Tang et al 2009)). These findings indicate the multiple mechanisms involved in anti-cancer effects of berberine on different tumor cell types

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