A Novel Mechanism of Cannabidiol in Suppressing Hepatocellular Carcinoma by Inducing GSDME Dependent Pyroptosis

Fugen Shangguan; Hongfei Zhou; Nengfang Ma; Shanshan Wu; Huimin Huang; Guihua Jin; Shijia Wu; Weilong Hong; Weiwei Zhuang; Hongping Xia; Linhua Lan

doi:10.3389/fcell.2021.697832

A Novel Mechanism of Cannabidiol in Suppressing Hepatocellular Carcinoma by Inducing GSDME Dependent Pyroptosis

Front Cell Dev Biol. 2021 Jul 19:9:697832. doi: 10.3389/fcell.2021.697832. eCollection 2021.

Authors

Fugen Shangguan¹, Hongfei Zhou¹, Nengfang Ma², Shanshan Wu³, Huimin Huang¹, Guihua Jin¹, Shijia Wu¹, Weilong Hong¹, Weiwei Zhuang¹, Hongping Xia^{1

4}, Linhua Lan¹

Affiliations

¹ Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
² School of Life and Environmental Science, Wenzhou University, Wenzhou, China.
³ Medical Research Center, The First Affliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁴ Department of Pathology in the School of Basic Medical Sciences, The Affiliated Sir Run Run Hospital, State Key Laboratory of Reproductive Medicine, Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing, China.

Abstract

Cannabidiol (CBD), a phytochemical derived from Cannabis sativa L., has been demonstrated to exhibit promising anti-tumor properties in multiple cancer types. However, the effects of CBD on hepatocellular carcinoma (HCC) cells remain unknown. We have shown that CBD effectively suppresses HCC cell growth in vivo and in vitro, and induced HCC cell pyroptosis in a caspase-3/GSDME-dependent manner. We further demonstrated that accumulation of integrative stress response (ISR) and mitochondrial stress may contribute to the initiation of pyroptotic signaling by CBD. Simultaneously, CBD can repress aerobic glycolysis through modulation of the ATF4-IGFBP1-Akt axis, due to the depletion of ATP and crucial intermediate metabolites. Collectively, these observations indicate that CBD could be considered as a potential compound for HCC therapy.

Keywords: aerobic glycolysis; cannabidiol; hepatocellular carcinoma; integrative stress response; pyroptosis.