Stimulatory heterotrimeric GTP-binding protein augments cisplatin-induced apoptosis by upregulating Bak expression in human lung cancer cells.
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.
Choi
Yoon Jung
YJ
Department of Biochemistry and Molecular Biology, Laboratory of Cellular Signaling, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Oh
Jung-Min
JM
Kim
So-Young
SY
Seo
Miran
M
Juhnn
Yong-Sung
YS