G Protein Alpha S Subunit Promotes Cell Proliferation of Renal Cell Carcinoma with Involvement of Protein Kinase A Signaling.

Heterotrimeric G proteins, which are composed of G and G subunits, transduce signals sensed by the coupled surface receptors. Aberrant expressions of G proteins have been observed in many cancer types. This study aimed to determine the expression level of the stimulatory G protein alpha S subunit (Gs, the main transcript encoded by the GNAS locus) and its biological function in renal cell carcinoma (RCC). Western blotting and quantitative reverse transcription-PCR results show that Gs expression dramatically increased in RCC cell lines (ACHN, GRC-1, and 786-O) compared to normal renal epithelial cells HK-2. Knockdown of Gs by small interfering RNA (siRNA) caused a significant inhibition on proliferation of ACHN cells as indicated by MTT assay and colony formation assay. Overexpression of Gs in HK-2 cells promoted cell proliferation and led to a higher level of intracellular cyclic adenosine monophosphate (cAMP) in response to parathyroid hormone (PTH) compared to the cells transfected with empty vector. Notably, the growth of HK-2 cells overexpressing Gs was efficiently inhibited in the presence of protein kinase A (PKA) inhibitor H89. Furthermore, in a xenograft model by subcutaneous injection of ACHN cells, tumor growth was also suppressed by H89. Taken together, these results suggest that Gs plays a tumor-promoting role in RCC and possibly acts through a PKA-dependent pathway. Our findings may provide new clues for target therapy for RCC in the future.