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Stimulatory heterotrimeric GTP-binding protein augments cisplatin-induced apoptosis by upregulating Bak expression in human lung cancer cells

, : Stimulatory heterotrimeric GTP-binding protein augments cisplatin-induced apoptosis by upregulating Bak expression in human lung cancer cells. Cancer Science 100(6): 1069-1074

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.


PMID: 19320642

DOI: 10.1111/j.1349-7006.2009.01136.x

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