Leukotriene A4 hydrolase as a target for cancer prevention and therapy.

Abstract

Leukotriene A4 hydrolase (LTA4H) is a bifunctional zinc enzyme with the activities of epoxide hydrolase and aminopeptidase. As an epoxide hydrolase, LTA4H catalyzes the hydrolysis of the epoxide LTA4 to the diol, leukotriene B4 (LTB4), which mainly functions as a chemoattractant and an activator of inflammatory cells. As an aminopeptidase, LTA4H may process peptides related to inflammation and host defense. In a chronic inflammation-associated animal model of esophageal adenocarcinoma, we have shown that LTA4H was overexpressed in tumor as compared to normal tissues. Bestatin, an LTA4H inhibitor, suppresses tumorigenesis in this animal model. Since LTA4H has long been regarded as an anti-inflammatory target, we propose LTA4H as a target for prevention and therapy of cancers, especially those associated with chronic inflammation. Here we review the gene structure, expression, regulation and functions of LTA4H, as well as its involvement in carcinogenesis. We believe LTA4H/LTB4 may play an important role in chronic inflammation associated carcinogenesis by at least two mechanisms: a) the inflammation-augmenting effect on inflammatory cells through positive feedback mediated by its receptors and downstream signaling molecules; and b) the autocrine growth-stimulatory effect of LTB4 produced by epithelial cells, and the paracrine growth-stimulatory effect of LTB4 produced by inflammatory cells, on precancerous and cancer cells. Based on our present knowledge, inhibitors of LTA4H or antagonists of LTB4 receptors may be used alone or in combination with other agents (e.g., cyclooxygenase 2 inhibitors) in cancer prevention and treatment trials to test their effectiveness.