cGMP-Dependent Protein Kinases as Potential Targets for Colon Cancer Prevention and Treatment

Abstract

In recent years, several antitumor signaling pathways mediated by the cGMP-dependent protein kinases have been identified in colon cancer cells. This review aims to present the mounting evidence in favor of cGMP/protein kinase G (PKG) signaling as a therapeutic strategy in colon cancer. The homeostatic and tumor suppressive effects of cGMP in the intestine are uncontested, but the signaling details are not understood. PKG is the central cGMP effector, and can block proliferation and tumor angiogenesis by inhibiting β-catenin/TCF and SOX9 signaling. Therapeutic activation of cGMP/PKG offers a promising avenue for the prevention and treatment of colon cancer, but additional preclinical studies are needed to fully understand the potential of this system.

cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium

“…57,58 It is possible that short-term FoxO activation favors protective antioxidant gene expression, but more prolonged ROS challenge might lead to reduced mitochondrial function as a feedback mechanism at the cost of butyrate utilization. The contention that cGMP promotes mitochondrial biogenesis, as reported previously, 38 is ostensibly at odds with FoxO suppressing cMyc function. However, it is possible that the increased mitochondrial biogenesis observed previously in response to cGMP could be indirect, and associated with increased differentiation rather than a direct effect on the mitochondria.…”

“…Several of these studies have suggested that inhibition of b-catenin/T-cell factor by type 1 PKG (PKG1) is a possible growth-inhibitory mechanism in colon cancer cells. 38 More recently, type 2 PKG (PKG2) has also been reported to inhibit proliferation in gastric cancer cells lines by a mechanism involving inhibition of extracellular signal regulated kinase (ERK) and AKT signaling pathways. 29,39,40 To determine whether PKG2 can also inhibit these pathways in colon cancer cells, we made use of cell lines made inducible for PKG2 expression that have been characterized previously.…”

“…It has been suggested that by suppressing AKT in the colon epithelium, cGMP shifts metabolism away from glycolysis in favor of increased mitochondrial biogenesis and oxidative phosphorylation. 38 This would be expected to facilitate the utilization of short chain fatty acids generated by commensal bacteria, which are the primary energy source of colonocytes. 55 However, this would also increase redox stress, particularly at the luminal border, where oxygen levels are limited.…”

Elucidation of the therapeutic enhancer mechanism of poly-S-nitrosated human serum albumin against multidrug-resistant tumor in animal models

“…7). Previously, several antitumor NO-cGMP-dependent signaling pathways such as protein kinase G have been identified in cancer cells [23][24][25][26][27]. There is evidence that the activation of NO-cGMP-dependent Fig.…”

Emergent Concepts from the Intestinal Guanylyl Cyclase C Pathway

“…For instance, cGMP binding to two allosteric sites present at the amino-terminal region of PKG II fully activates the enzyme and induces phosphorylation and opening of the cystic fibrosis transmembrane conductance regulator (CFTR), a pivotal mechanism underlying control of intestinal fluid homeostasis (Pfeifer et al, 1999). For an in depth discussion on the regulation of the various biochemical cGMP-dependent targets, such as the CFTR channel, the reader is referred to other comprehensive reviews (Browning et al, 2010;Lucas et al, 2000;. Here, the focus will be on those molecular elements of the GCC and cGMP pathway that affect the epithelial cell phenotype, including its proliferative, morphogenetic and migratory attributes that greatly influence the crypt-villus homeostasis and the process of neoplastic transformation.…”