Cyclooxygenase-deficient pancreatic cancer cells use exogenous sources of prostaglandins

Genes that are differentially expressed in pancreatic cancers and under epigenetic regulation are of considerable biological and therapeutic interest. We used global gene expression profiling and epigenetic treatment of pancreatic cell lines including pancreatic cancer cell lines, pancreatic cancer-associated fibroblasts, and cell lines derived from nonneoplastic pancreata. We examined expression and epigenetic alterations of cyclooxygenase-1 (COX-1) and COX-2 in pancreatic cancers and normal pancreas and performed proliferation, knockdown, and coculture experiments to understand the role of stromal sources of prostaglandins for pancreatic cancers. We identify COX-1 as a gene under epigenetic regulation in pancreatic cancers. We find that COX-1 expression is absent in many pancreatic cancer cells and some of these cancers also lack COX-2 expression. Suspecting that such cancers must rely on exogenous sources of prostaglandins, we show that pancreatic cancer stromal cells, such as fibroblasts expressing COX-1 and COX-2, are a likely source of prostaglandins for pancreatic cancer cells deficient in COX. Knocking down the prostaglandin transporter multidrug resistance-associated protein-4 in fibroblasts suppresses the proliferation of cocultured pancreatic cancer cells lacking COX. Pancreatic cancers that lack COX can use exogenous sources of prostaglandins. Blocking multidrug resistance-associated protein-4 may be a useful therapeutic strategy to deplete COX-deficient pancreatic cancers of prostaglandins.