Abstract
A relationship between cyclic adenosine 3′, 5′-monophosphate (cAMP) levels and brain tumor biology has been evident for nearly as long as cAMP and its synthetase, adenylate cyclase (ADCY) have been known. The importance of the pathway in brain tumorigenesis has been demonstrated in vitro and in multiple animal models. Recently, we provided human validation for a cooperating oncogenic role for cAMP in brain tumorigenesis when we found that SNPs in ADCY8 were correlated with glioma (brain tumor) risk in individuals with Neurofibromatosis type 1 (NF1). Together, these studies provide a strong rationale for targeting cAMP in brain tumor therapy. However, the cAMP pathway is well-known to be sexually dimorphic, and SNPs in ADCY8 affected glioma risk in a sex-specific fashion, elevating the risk for females while protecting males. The cAMP pathway can be targeted at multiple levels in the regulation of its synthesis and degradation. Sex differences in response to drugs that target cAMP regulators indicate that successful targeting of the cAMP pathway for brain tumor patients is likely to require matching specific mechanisms of drug action with patient sex.
Highlights
A relationship between cyclic adenosine 3′, 5′-monophosphate levels and brain tumor biology has been evident for nearly as long as cAMP and its synthetase, adenylate cyclase (ADCY) have been known
We provided human validation for a cooperating oncogenic role for cAMP in brain tumorigenesis when we found that single nucleotide polymorphism (SNP) in ADCY8 were correlated with glioma risk in individuals with Neurofibromatosis type 1 (NF1)
High ADCY activity and cAMP levels were found in benign brain tumors, while lower ADCY activity and cAMP levels were correlated with greater degrees of malignancy
Summary
Differences in cAMP synthesis arise through differences in expression, subcellular localization and activation of nine different membrane bound ADCYs and one soluble ADCY (Cooper and Tabbasum, 2014). Variation in stimulation and inhibition by heterotrimeric G protein subunits, calcium, multiple protein kinase C isoforms and calcium/calmodulindependent protein kinase results in unique regulatory “codes” for activation of different ADCY isoforms (Sunahara and Taussig, 2002; Cooper and Tabbasum, 2014) These non-overlapping mechanisms of regulation potentially create alternate landscapes for the interaction between primary oncogenic events in brain tumorigenesis and total ADCY activity. Deletion of the alpha subunit of the stimulatory heterotrimeric G protein Gs resulted in SHH-driven medulloblastoma (He et al, 2014) Together these genetically engineered mouse models indicate that diminution in the ability to elevate cAMP levels within the granule neuron. Blockade of CXCR4 signaling, and elevation of cAMP levels, with specific small molecule antagonists has potent anti-tumor effects in intracranial xenograft models of SHH driven medulloblastoma (Rubin et al, 2003; Yang et al, 2007; Barone et al, 2014)
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