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EPAC-RAP1 Axis-mediated Switch in the Response of Primary and Metastatic Melanoma to cyclic AMP
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Abstract
Cyclic AMP (cAMP) is an important second messenger that regulates a wide range of physiological processes. In mammalian cutaneous melanocytes, cAMP-mediated signaling pathways activated by G-protein coupled receptors (GPCRs), 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. Whereas mutations in mitogen activated protein kinase (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 pharmacological inhibition of the cAMP effector protein kinase A (PKA). Pharmacological inhibition and small interfering RNA (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.