Essential role of the cGMP/PKG signaling pathway in regulating the proliferation and survival of human renal carcinoma cells

Abstract

Phosphodiesterase type 5 (PDE5) plays a key role in regulating the intracellular cyclic GMP (cGMP) concentration, which influences anti-proliferative and pro-apoptotic mechanisms in multiple carcinomas. PDE5 inhibitors, such as exisulind and its analogs have anticancer activities. In this study, we found that suppressing PDE5 gene expression by PDE5 siRNA inhibited cell proliferation and induced apoptosis in OS-RC-2 human renal cell carcinoma cells. These effects were enhanced by 8-Br-cGMP, a cell membrane permeable cGMP derivative, and were inhibited by KT5823, a protein kinase G (PKG) inhibitor, indicating that PKG was activated by intracellular cyclic GMP. In addition, there was a reduction in both the mRNA and protein expression of cyclin D1, while p21 protein expression was increased; the reduction in cyclin D1 expression was blocked by the proteasome inhibitor, MG132, or c-Jun N-terminal kinase (JNK) inhibitor; both β-catenin and JNK were phosphorylated by activated PKG. Furthermore, p21 protein expression was decreased in Sp1 siRNA transfected-cells treated with 8-Br-cGMP, indicating that p21 may be partly controlled by the PKG activation through Sp1. Furthermore, we found that PKG Iβ was responsible for the anticancer activities. Our findings indicate that the downregulation of PKG-activated genes, such as cyclin D1 partly accounts for the pro-apoptotic effects in PDE5 siRNA-transfected OS-RC-2 cells.

Comprehensive analysis of multi Ewing sarcoma microarray datasets identifies several prognosis biomarkers

“…The cGMP-PKG signaling pathway was significantly enriched in the DEGs of clusters 1 and 3 and proved to be closely associated with tumor progression. Upregulated cGMP and its downstream protein kinase G (PKG) are known to inhibit the proliferation and induce the apoptosis of colon cancer cells, and activated intracellular cGMP-PKG pathway is known to enhance the degradation of β-catenin in SW480 colon cancer cells ( 37 – 39 ). Calcium signaling pathways were observed in clusters 1, 3 and 6; these signaling pathways serve a significant role in the cell apoptosis process ( 35 ).…”

The Impact of the Nitric Oxide (NO)/Soluble Guanylyl Cyclase (sGC) Signaling Cascade on Kidney Health and Disease: A Preclinical Perspective

“…In addition, following treatment with the PDE5 inhibitor the animals also showed increased baroreceptor sensitivity and decreased oxidative stress. Interestingly, apart from cardio-renal pathologies, a PDE5 siRNA was also shown to inhibit proliferation and survival of human renal carcinoma cells [ 88 ].…”

Phosphodiesterase type 5 and cancers: progress and challenges

“…The addition of PDE5 inhibitors to multiple existing treatment regimens, including doxorubicin, mitomycin C, gemcitabine, cisplatin and paclitaxel, significantly enhanced chemotherapy lethality by stimulating the extrinsic apoptosis pathway via CD95 and by promoting autophagy through RIP-1 (receptor interacting protein 1) in bladder and pancreatic cancer cell lines [ 156 ]. In human renal carcinoma cell lines, suppression of PDE5 gene expression by PDE5 siRNA reduced cell proliferation and induced apoptosis through cGMP-PKG activation [ 273 ]. Sildenafil in combination with C-type natriuretic peptide synergistically inhibited proliferation of rhabdomyosarcoma cells and suppressed tumor growth in vivo [ 274 ].…”