title: Stimulatory heterotrimeric GTP-binding protein augments cisplatin-induced apoptosis by upregulating Bak expression in human lung cancer cells.
abstract: The present study aimed to investigate the effect of the stimulatory heterotrimeric GTP-binding (Gs) protein signaling system on cisplatin-induced apoptosis of lung cancer cells and its underlying mechanism as an attempt to develop a novel strategy to improve the therapeutic efficacy of cisplatin. Overexpression of the constitutively active alpha subunit of Gs (GalphasQL) in A549 human lung cancer cells increased cisplatin-induced apoptosis, and knockdown of Galphas with small hairpin RNA decreased the percentage of apoptotic cells. GalphasQL increased the expression of the proapoptotic proteins B-cell leukemia/lymphoma-2 genes (Bcl-2) homologous antagonist killer protein (Bak) and Bcl-2 associated X protein (Bax), and decreased the expression of the antiapoptotic proteins Bcl-2 and Bcl-Xlong protein. Knockdown of Bak blocked the augmentative effects of GalphasQL. GalphasQL decreased the degradation rate of the Bak protein, and increased Bak mRNA transcript levels. GalphasQL increased Bak-luciferase activity in a protein kinase A and cyclic AMP response element-dependent manner. GalphasQL also augmented cisplatin-induced apoptosis of H1299 human lung cancer cells that lack functional p53. From this study, it is concluded that Galphas augments cisplatin-induced apoptosis of lung cancer cells partially through upregulating Bak expression by increasing transcription and by decreasing the rate of protein degradation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Laboratory of Cellular Signaling, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yoon Jung
authors.initials: YJ
authors.lastname: Choi
authors.forename: Jung-Min
authors.initials: JM
authors.lastname: Oh
authors.forename: So-Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Miran
authors.initials: M
authors.lastname: Seo
authors.forename: Yong-Sung
authors.initials: YS
authors.lastname: Juhnn