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 α subunit of Gs (GαsQL) in A549 human lung cancer cells increased cisplatin‐induced apoptosis, and knockdown of Gαs with small hairpin RNA decreased the percentage of apoptotic cells. GαsQL 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 GαsQL. GαsQL decreased the degradation rate of the Bak protein, and increased Bak mRNA transcript levels. GαsQL increased Bak‐luciferase activity in a protein kinase A and cyclic AMP response element‐dependent manner. GαsQL also augmented cisplatin‐induced apoptosis of H1299 human lung cancer cells that lack functional p53. From this study, it is concluded that Gαs augments cisplatin‐induced apoptosis of lung cancer cells partially through upregulating Bak expression by increasing transcription and by decreasing the rate of protein degradation. (Cancer Sci 2009; 100: 1069–1074)