Targeting Cyclic AMP Signalling in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a major healthcare problem worldwide, representing one of the leading causes of cancer mortality. Since there are currently no predictive biomarkers for early stage diagnosis, HCC is detected only in advanced stages and most patients die within one year, as radical tumour resection is generally performed late during the disease. The development of alternative therapeutic approaches to HCC remains one of the most challenging areas of cancer. This review focuses on the relevance of cAMP signalling in the development of hepatocellular carcinoma and identifies the modulation of this second messenger as a new strategy for the control of tumour growth. In addition, because the cAMP pathway is controlled by phosphodiesterases (PDEs), targeting these enzymes using PDE inhibitors is becoming an attractive and promising tool for the control of HCC. Among them, based on current preclinical and clinical findings, PDE4-specific inhibitors remarkably demonstrate therapeutic potential in the management of cancer outcomes, especially as adjuvants to standard therapies. However, more preclinical studies are warranted to ascertain their efficacy during the different stages of hepatocyte transformation and in the treatment of established HCC.

Keywords: EPAC; GPCR; HCC; PDE; PDE inhibitors; PKA; cancer; cyclase; hepatocyte; phosphodiesterase.

Figure 1

Schematic representation of cAMP formation/degradation and of cAMP target proteins. POPDC, Popeye domain containing protein, AC, adenylyl cyclase; Gs, stimulatory G protein; Gi, inhibitory G protein. CNGC, cyclic nucleotide-gated channels; EPAC, exchange protein directly activated by cAMP; Rap-GTP, GTP-binding Ras related protein; AKAP, A-kinase anchoring proteins; PDE, phosphodiesterase; PKA, cAMP-dependent protein kinase.

Figure 2

Schematic representation of the main pathways and down-stream effectors involved in cAMP signalling in HCC. GPCR, protein G coupled receptor; VPAC, vasoactive intestinal polypeptide receptor 1 or VIPR1; RA, retinoic acid; CREB, cAMP response element-binding protein; cdk2, cyclin-dependent kinase 2; GSK-3β glycogen synthase kinase 3β; ERK, extracellular-signal-regulated kinase.