The Role of Cyclic Nucleotide Signaling Pathways in Cancer: Targets for Prevention and Treatment

Abstract

For more than four decades, the cyclic nucleotides cyclic AMP (cAMP) and cyclic GMP (cGMP) have been recognized as important signaling molecules within cells. Under normal physiological conditions, cyclic nucleotides regulate a myriad of biological processes such as cell growth and adhesion, energy homeostasis, neuronal signaling, and muscle relaxation. In addition, altered cyclic nucleotide signaling has been observed in a number of pathophysiological conditions, including cancer. While the distinct molecular alterations responsible for these effects vary depending on the specific cancer type, several studies have demonstrated that activation of cyclic nucleotide signaling through one of three mechanisms—induction of cyclic nucleotide synthesis, inhibition of cyclic nucleotide degradation, or activation of cyclic nucleotide receptors—is sufficient to inhibit proliferation and activate apoptosis in many types of cancer cells. These findings suggest that targeting cyclic nucleotide signaling can provide a strategy for the discovery of novel agents for the prevention and/or treatment of selected cancers.

Expression and Function of Phosphodiesterase Type 5 in Human Breast Cancer Cell Lines and Tissues: Implications for Targeted Therapy

“…In addition, dysregulation of cGMP homeostasis was observed in various (patho)physiologic conditions, including cancers. Indeed, cGMP signaling, through activation of downstream effectors (i.e., cGMP-dependent protein kinase G-PKG, cyclic-nucleotide-gated ion channels) and/or crosstalk with cAMP pathways, appears to play an important role in promoting apoptosis and inhibiting proliferation of certain epithelial cells (6,7). Interestingly, PKG expression or cGMP levels are reduced in cancer cells and tissues compared with their normal counterparts (8,9).…”

Restoration of Mitochondrial Dysfunction in 6-Hydroxydopamine Induced Parkinson’s disease: a Complete Review

“…The second messenger concept of signaling was developed with the fi nding of cAMP and its ability to infl uence metabolism, cell shape and gene transcription (via reversible protein phosphorylations) [326]. cAMP exerts an important role as second messenger molecule controlling multiple cellular processes in the brain [327]. …”

Synthesis, 18F-Radiolabelling and Biological Characterization of Novel Fluoroalkylated Triazine Derivatives for in Vivo Imaging of Phosphodiesterase 2A in Brain via Positron Emission Tomography

“…Due to hydrolysis of the cyclic nucleotides, PDEs affect the second messenger signaling cascades of cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) [1,2]. Therefore, pharmacological inhibition of PDEs has the potential to enhance cyclic nucleotide signaling and can provide a strategy for the prevention or treatment of various diseases [2,[5][6][7][8].…”