Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: EPAC-RAP1 Axis-Mediated Switch in the Response of Primary and Metastatic Melanoma to Cyclic AMP.

Authors: Rodríguez, Carlos I; Castro-Pérez, Edgardo; Prabhakar, Kirthana; Block, Laura; Longley, B Jack; Wisinski, Jaclyn A; Kimple, Michelle E; Setaluri, Vijayasaradhi

Published In Mol Cancer Res, (2017 12)

Abstract: Cyclic AMP (cAMP) is an important second messenger that regulates a wide range of physiologic processes. In mammalian cutaneous melanocytes, cAMP-mediated signaling pathways activated by G-protein-coupled receptors (GPCR), like melanocortin 1 receptor (MC1R), play critical roles in melanocyte homeostasis including cell survival, proliferation, and pigment synthesis. Impaired cAMP signaling is associated with increased risk of cutaneous melanoma. Although mutations in MAPK pathway components are the most frequent oncogenic drivers of melanoma, the role of cAMP in melanoma is not well understood. Here, using the Braf(V600E)/Pten-null mouse model of melanoma, topical application of an adenylate cyclase agonist, forskolin (a cAMP inducer), accelerated melanoma tumor development in vivo and stimulated the proliferation of mouse and human primary melanoma cells, but not human metastatic melanoma cells in vitro The differential response of primary and metastatic melanoma cells was also evident upon pharmacologic inhibition of the cAMP effector protein kinase A. Pharmacologic inhibition and siRNA-mediated knockdown of other cAMP signaling pathway components showed that EPAC-RAP1 axis, an alternative cAMP signaling pathway, mediates the switch in response of primary and metastatic melanoma cells to cAMP. Evaluation of pERK levels revealed that this phenotypic switch was not correlated with changes in MAPK pathway activity. Although cAMP elevation did not alter the sensitivity of metastatic melanoma cells to BRAF(V600E) and MEK inhibitors, the EPAC-RAP1 axis appears to contribute to resistance to MAPK pathway inhibition. These data reveal a MAPK pathway-independent switch in response to cAMP signaling during melanoma progression.Implications: The prosurvival mechanism involving the cAMP-EPAC-RAP1 signaling pathway suggest the potential for new targeted therapies in melanoma. Mol Cancer Res; 15(12); 1792-802. ©2017 AACR.

PubMed ID: 28851815 Exiting the NIEHS site

MeSH Terms: Adenylyl Cyclases/drug effects; Adenylyl Cyclases/genetics; Animals; Cell Line, Tumor; Colforsin/administration & dosage; Cyclic AMP/genetics; Cyclic AMP/metabolism; Guanine Nucleotide Exchange Factors/genetics*; Humans; Melanoma/drug therapy*; Melanoma/genetics; Melanoma/pathology; Mice; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases/genetics; Neoplasm Metastasis; PTEN Phosphohydrolase/genetics*; Proto-Oncogene Proteins B-raf/genetics*; Receptor, Melanocortin, Type 1/genetics; Signal Transduction/drug effects; Telomere-Binding Proteins/genetics*

Back
to Top