Cannabidiol promotes apoptosis via regulation of XIAP/Smac in gastric cancer

Soyeon Jeong,Hye Kyeong Yun,Duane T Smoot,Yoo Jin Na,Bu Gyeom Kim,Sang Cheul Oh,Sun Il Lee,Jun Young Heo,Min Jee Jo,Dae-Hee Lee,Jung Lim Kim,Bo Ram Kim,Dae Hyun Kim,Jeongsu Han,Dae Yeong Kim,Hassan Ashktorab,Seong Hye Park,Yoon A Jeong,Han Do Kim

doi:10.1038/s41419-019-2001-7

Abstract

According to recent studies, Cannabidiol (CBD), one of the main components of Cannabis sativa, has anticancer effects in several cancers. However, the exact mechanism of CBD action is not currently understood. Here, CBD promoted cell death in gastric cancer. We suggest that CBD induced apoptosis by suppressing X-linked inhibitor apoptosis (XIAP), a member of the IAP protein family. CBD reduced XIAP protein levels while increasing ubiquitination of XIAP. The expression of Smac, a known inhibitor of XIAP, was found to be elevated during CBD treatment. Moreover, CBD treatment increased the interaction between XIAP and Smac by increasing Smac release from mitochondria to the cytosol. CBD has also been shown to affect mitochondrial dysfunction. Taken together, these results suggest that CBD may have potential as a new therapeutic target in gastric cancer.

Highlights

Cannabidiol (CBD) is one of the Cannabis sativa extracts that does not contain psychoactive components and is considered more useful than tetrahydrocannabinol, a psychotropic active cannabinoid, in clinical applications[1,2]
Our results show that CBD induces mitochondrial dysfunction and regulates second mitochondria-derived activator of caspase (Smac)/X-linked inhibitor apoptosis (XIAP) leading to apoptosis, suggesting that Smac/XIAP regulation using CBD can be potentially utilized for the treatment of gastric cancer
We found that cell proliferation decreased following CBD treatment, but it had no effect in gastric normal cells

Summary

Introduction

Cannabidiol (CBD) is one of the Cannabis sativa extracts that does not contain psychoactive components and is considered more useful than tetrahydrocannabinol, a psychotropic active cannabinoid, in clinical applications[1,2]. CBD is known to have antitumor activity against Noxa activation, inhibition of mTOR/cyclin D1, and Gprotein-coupled receptors/mitogen-activated protein kinase pathway in various cancers such as pancreatic[3,4], glioblastoma[1], colorectal[5], and breast cancer[6]. It has beneficial effects on brain function, metabolism, and pain reduction[7,8,9]. The main negative regulator of XIAP is the second mitochondria-derived activator of caspase (Smac). Smac is normally present in the mitochondria and when apoptosis occurs it is released into the cytosol, and the signal peptide of the N-terminal region is removed and becomes an active form[15]. Activated Smac competitively blocks the caspase-binding sites of XIAP and induces the caspase cascade, resulting in further apoptosis[16]

Methods

Results

Conclusion