beta-lapachone-Induced Apoptosis of Human Gastric Carcinoma AGS Cells Is Caspase-Dependent and Regulated by the PI3K/Akt Pathway.
- Author:
Hai Yang YU
1
;
Sung Ok KIM
;
Cheng Yun JIN
;
Gi Young KIM
;
Wun Jae KIM
;
Young Hyun YOO
;
Yung Hyun CHOI
Author Information
1. College of Natural Resources and Life Science, Dong-A University, Busan 604-714, Republic of Korea.
- Publication Type:In Vitro ; Original Article
- Keywords:
beta-lapachone;
Apoptosis;
Caspase;
PI3K/Akt
- MeSH:
Apoptosis*;
Caspase 3;
Caspase 8;
Caspase 9;
Cell Death;
Cell Proliferation;
Chromatin;
Cytochromes c;
Down-Regulation;
Humans;
Membrane Potentials;
Phosphatidylinositol 3-Kinase;
Poly(ADP-ribose) Polymerases;
Up-Regulation
- From:Biomolecules & Therapeutics
2014;22(3):184-192
- CountryRepublic of Korea
- Language:English
-
Abstract:
beta-lapachone is a naturally occurring quinone that selectively induces apoptotic cell death in a variety of human cancer cells in vitro and in vivo; however, its mechanism of action needs to be further elaborated. In this study, we investigated the effects of beta-lapachone on the induction of apoptosis in human gastric carcinoma AGS cells. beta-lapachone significantly inhibited cellular proliferation, and some typical apoptotic characteristics such as chromatin condensation and an increase in the population of sub-G1 hypodiploid cells were observed in beta-lapachone-treated AGS cells. Treatment with beta-lapachone caused mitochondrial transmembrane potential dissipation, stimulated the mitochondria-mediated intrinsic apoptotic pathway, as indicated by caspase-9 activation, cytochrome c release, Bcl-2 downregulation and Bax upregulation, as well as death receptor-mediated extrinsic apoptotic pathway, as indicated by activation of caspase-8 and truncation of Bid. This process was accompanied by activation of caspase-3 and concomitant with cleavage of poly(ADP-ribose) polymerase. The general caspase inhibitor, z-VAD-fmk, significantly abolished beta-lapachone-induced cell death and inhibited growth. Further analysis demonstrated that the induction of apoptosis by beta-lapachone was accompanied by inactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. The PI3K inhibitor LY29004 significantly increased beta-lapachone-induced apoptosis and growth inhibition. Taken together, these findings indicate that the apoptotic activity of beta-lapachone is probably regulated by a caspase-dependent cascade through activation of both intrinsic and extrinsic signaling pathways, and that inhibition of the PI3K/Akt signaling may contribute to beta-lapachone-mediated AGS cell growth inhibition and apoptosis induction.
