?-Thujaplicin induces autophagic cell death, apoptosis, and cell cycle arrest through ROS-mediated Akt and p38/ERK MAPK signaling in human hepatocellular carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC), a common liver malignancy worldwide, has high morbidity and mortality. ?-Thujaplicin, a tropolone derivative, has been used in some health-care products and clinical adjuvant drugs, but its use for HCC is unknown. In this study, we found that ?-Thujaplicin inhibits the growth of HCC cells, but not normal liver cells, with nanomolar potency. Mechanistically, we found that ?-Thujaplicin could induce autophagy, as judged by western blot, confocal microscopy, and transmission electron microscopy. Further using ?-Thujaplicin combined with an autophagy blocker or agonist treatment HepG2 cells, we found that ?-Thujaplicin induced autophagic cell death (ACD) mediated by ROS caused inhibition of the Akt-mTOR signaling pathway. Moreover, ?-Thujaplicin triggered HepG2 apoptosis and increased cleaved PARP1, cleaved caspase-3, and Bax/Bcl-2 ratio, which indicated that ?-Thujaplicin induced apoptosis mediated by the mitochondrial-dependent pathway. We also found that increased expression of p21 and decreased expression of CDK7, Cyclin D1, and Cyclin A2 participating in ?-Thujaplicin caused the S-phase arrest. It seems that ?-Thujaplicin exerts these functions by ROS-mediated p38/ERK MAPK but not by JNK signaling pathway activation. Consistent with in vitro findings, our in vivo study verified that ?-Thujaplicin treatment significantly reduced HepG2 tumor xenograft growth. Taken together these findings suggest that ?-Thujaplicin have an ability of anti-HCC cells and may conducively promote the development of novel anti-cancer agents.

SUBMITTER: Zhang G 

PROVIDER: S-EPMC6420571 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature