Potential Upstream Regulators of Cannabinoid Receptor 1 Signaling in Prostate Cancer: A Bayesian Network Analysis of Data From a Tissue Microarray

BACKGROUND: The endocannabinoid system regulates cancer cell proliferation, and in prostate cancer a high cannabinoid CB(1) receptor expression is associated with a poor prognosis. Down-stream mediators of CB(1) receptor signaling in prostate cancer are known, but information on potential upstream regulators is lacking. RESULTS: Data from a well-characterized tumor tissue microarray were used for a Bayesian network analysis using the max-min hill-climbing method. In non-malignant tissue samples, a directionality of pEGFR (the phosphorylated form of the epidermal growth factor receptor) → CB(1) receptors were found regardless as to whether the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) was included as a parameter. A similar result was found in the tumor tissue, but only when FAAH was included in the analysis. A second regulatory pathway, from the growth factor receptor ErbB2 → FAAH was also identified in the tumor samples. Transfection of AT1 prostate cancer cells with CB(1) receptors induced a sensitivity to the growth-inhibiting effects of the CB receptor agonist CP55,940. The sensitivity was not dependent upon the level of receptor expression. Thus a high CB(1) receptor expression alone does not drive the cells towards a survival phenotype in the presence of a CB receptor agonist. CONCLUSIONS: The data identify two potential regulators of the endocannabinoid system in prostate cancer and allow the construction of a model of a dysregulated endocannabinoid signaling network in this tumor. Further studies should be designed to test the veracity of the predictions of the network analysis in prostate cancer and other solid tumors. Prostate 74:1107–1117, 2014. © 2014 The Authors. The Prostate published by Wiley Periodicals, Inc.