OVEREXPRESSION OF ADENYLATE CYCLASE ISOFORMS ALTERS CELL SIGNALING PATHWAYS IN NF1-NULL MALIGNANT PERIPHERAL NERVE SHEATH TUMORS

Abstract

The second messenger, cyclic-AMP (cAMP), is produced by ten adenylate cyclase (ADCY) isoforms. Previous studies indicate that ADCY isoforms may lead to either activation or inhibition of cAMP-dependent protein kinase (PKA), cAMP expression is increased in response to neurofibromin (NF1) mutations, and malignant peripheral nerve sheath tumors (MPNST) express more ADCY isoforms. ADCY expression and function are modulated by four adenosine receptors (ADORA), which have different effects on ADCY. We aimed to overexpress ADCY 3, 6, 7, and 9 in different cell lines to dissect the mechanism of how cAMP expression is altered after NF1 loss. Overexpression of ADCY 7 significantly affected PKA activity. Overexpression of ADCY 9 led to increased expression of ADORA 1, 2B, and 3 in MPNST cells. Overexpressed ADCY 3 and 7 increased ADORA 3 expression as well. These data indicate that changes in ADCY and ADORA expression in MPNSTs may account for changes in cAMP expression after loss of NF1.