Primers on molecular pathways - lipoxygenases: their role as an oncogenic pathway in pancreatic cancer

Different evidence supports a functional role of enzymes involved in lipid metabolic pathways, such as lipoxygenases (LOXs) and their metabolite derivatives, in carcinogenesis. LOX enzymes catalyze the dioxygenation of arachidonic acid into hydroxyperoxyeicosatetraenoic acids, which is followed by their conversion to their corresponding eicosanoids as hydroxyeicosatetraenoic acids, leukotrienes, lipoxins and hepoxilins, which in turn act as cellular messengers. Subcellular LOX enzyme localization varies according to the LOX and cellular type regulating different cell functions. LOX enzymes or their products may exert their biological effects in different modes, either intracellular or in other cells. Numerous clinical studies on expression of LOXs in human tumors as well as in animal models indicate different roles of distinct LOX isoforms in carcinogenesis. In fact, different LOXs exhibit either protumorigenic or antitumorigenic activities and modulate the tumor response in a tissue-specific manner. Moreover, the LOX pathways are involved in the spread and metastasis of several cancers, including pancreas, through the activation of several cellular signaling pathways which modify gene expression affecting cellular proliferation, survival, migration and extracellular matrix production. In this review we focus on the important role and different mechanisms of action of LOX pathways in the regulation of pancreatic cancer initiation and progression. A novel approach for pancreatic cancer chemoprevention would involve targeting LOX activities, alone or in combination with other pathways as a major anticancer strategy.