Biomol Ther.  2014 May;22(3):184-192.

beta-lapachone-Induced Apoptosis of Human Gastric Carcinoma AGS Cells Is Caspase-Dependent and Regulated by the PI3K/Akt Pathway

• Yu HY
• Kim SO
• Jin CY
• Kim GY
• Kim WJ
• Yoo YH
• Choi YH

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.

Keyword

beta-lapachone; Apoptosis; Caspase; PI3K/Akt

MeSH Terms

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
Caspase 3
Caspase 8
Caspase 9
Chromatin
Cytochromes c
Phosphatidylinositol 3-Kinase
Poly(ADP-ribose) Polymerases