Fig. 7

Schematic representation of the interplay of COX-2 and CYP19A1 in the asbestos cancerogenesis. Upon inhalation of asbestos fibers, mesothelial and inflammatory cells release a variety of cytokines that inhibit asbestos-induced cytotoxicity and induce inflammation. PGE2 is abundantly produced in the region of inflammation. PGE2-mediated activation of EP receptors leads to enhanced the cAMP/PKA and phosphatidylinositol 3-kinase (PI3K) signaling pathways. increased in cyclic adenosine monophosphate (cAMP) production activates protein kinase A (PKA) -CREB dependent expression of genes including COX-2 and CYP19A1. AKT activation (pAKT) induces the CREB activation (pCREB) resulting in increased CYP19A1 and COX-2 transcription and activities. This lead to enhanced E2 and PGE2 biosynthesis. The local concentrations of E2 upregulates CYP19A1 and COX-2 and PGE2 induces CYP19A1 and COX-2 and establishes a positive-feedback loop in favor of continuous E2 and PGE2 formation that results in increased proliferation of tumor cells and inflammation that ultimately leads to the onset of MPM. The combined use of rofecoxib and exemestane by reducing the levels of PGE2 and E2, respectively and the activation of AKT (pAKT) reduces inflammation and cell proliferation