Betulin induces cytochrome c release and apoptosis in colon cancer cells via NOXA

Abstract

Betulin is a common triterpene that can be readily obtained from various plants, particularly birch trees, in their natural environment. Specific tumor cells are sensitive to betulin, whereas healthy cells are not. Betulin was observed to stimulate programmed cell death of various cancer cell lines; however, the precise molecular mechanism of action of betulin remains unknown. The present study used colon cancer cells, in which mass apoptosis triggered by betulin was identified, and the apoptotic process was demonstrated to occur via the activation of caspase-3 and -9 pathways. In addition, release of cytochrome c was detected. Furthermore, the pro-apoptotic member of the Bcl-2 protein family, NOXA, was induced following treatment with betulin, and the downregulation of NOXA markedly suppressed the release of cytochrome and apoptosis in colon cancer cells. Conversely, the overexpression of NOXA further enhanced betulin-induced apoptosis. The present study therefore offers novel insights into the mechanism of action of the natural compound betulin against tumors.

Enhanced Accumulation of Betulinic Acid in Transgenic Hairy Roots of Senna obtusifolia Growing in the Sprinkle Bioreactor and Evaluation of Their Biological Properties in Various Biological Models

“…Zhou et al. proved also that betulin is able to stimulate programmed cell death in colon cancer cells, demonstrating that the overexpression of NOXA enhanced betulin‐induced apoptosis [66] . Additionally, Wick et al.…”

Betulin Inhibits Lung Metastasis by Inducing Cell Cycle Arrest, Autophagy, and Apoptosis of Metastatic Colorectal Cancer Cells

“…Although betulin induces cell cycle arrest and autophagy, it has a meagre effect compared to reduction of CRC cell viability. Several studies have reported that betulin shows selective inhibitory effects on proliferation of several cancer cells by inducing caspase-3-and caspase-9-mediated apoptosis [31][32][33]. In addition, betulin can regulate expressions of Bcl-2 and Bax in gastric and cervical cancer cells [33,34].…”

The Proteomics and Metabolomics Analysis for Screening the Molecular Targets of Action of β-Eudesmol in Cholangiocarcinoma

“…Cytc, the hemoprotein located in cell mitochondria, plays role in mitochondrial electron transport, cardiolipin peroxidation (Kagan et al, 2005), ROS formation, and cell apoptosis (Cai et al, 1998). Regarding cell apoptosis, several compounds such as tamoxifen (an anticancer drug for breast cancer) and botulin (triterpene from plants, e.g., birch trees) induce the release of Cytc from mitochondria in a dose-dependent manner (Hassan et al, 2018;Zhou et al, 2018). BAG3, the protein belonged to the member of BAG family, plays a role in the protection of cells from the apoptosis process by stabilizing antiapoptotic Bcl-2 family proteins as bcl-2 and bcl-XL (Kim et al, 2013).…”