Role of lipoxygenase pathways in the regulation of pancreatic cancer cell proliferation and survival

Pancreatic cancer is characterized by a poor prognosis and lack of response to conventional therapy. Many studies have shown an association of pancreatic cancer development and growth with high dietary fat intake, especially intake of n-6 polyunsaturated fats. A growing body of evidence suggests that specific metabolites of arachidonic acid act as important elements in signaling pathways necessary for cancer cell transformation, growth and metastasis, via both cyclooxygenase (COX) and lipoxygenase (LOX) pathways. This review summarizes the current research status on the role of LOX on pancreatic cancer cell growth and apoptosis as well as the underlying signaling pathways involved. The proliferation of pancreatic cancer cells is inhibited by LOX inhibitors and stimulated by LOX metabolites. LOX inhibition even blocks growth stimulated by exogenous growth factors such as epidermal growth factor (EGF). Pancreatic cancer cell apoptosis (programmed cell death) is induced by blockade of either 5-LOX or 12-LOX pathways. Preliminary evidence suggests that the expression of both 5- and 12-lipoxygenases are upregulated in pancreatic cancer. The direct stimulation of pancreatic cancer cell proliferation by the metabolites of 5-LOX and 12-LOX (5-HETE and 12-HETE, respectively) is mediated by multiple signaling pathways, particularly the MEK/ERK signaling pathway but also involving intracellular tyrosine kinases. Thus, LOX pathways play an important role in pancreatic cancer cell proliferation and apoptosis and these pathways are likely to be valuable targets for development of therapeutics for this devastating disease.