Frontiers in Pharmacology (Dec 2010)
5-lipoxygenase: underappreciated role of a pro-inflammatory enzyme in tumourigenesis
Abstract
Leukotrienes (LTs) constitute a group of bioactive lipids generated by the 5-lipoxygenase (5-LO) pathway. An increasing body of evidence supports an acute role for 5-LO products already during the earliest stages of pancreatic, prostate and colorectal carcinogenesis. First, several independent studies documented an overexpression of 5-LO in primary tumour cells as well as in established cancer cell lines. Second, addition of 5-LO products to cultured tumour cells also led to increased cell proliferation and activation of anti-apoptotic signaling pathways. 5-LO antisense technology approaches demonstrated impaired tumour cell growth due to reduction of 5-LO expression. Lastly, pharmacological inhibition of 5-LO potently suppressed tumour cell growth by inducing cell cycle arrest and triggering cell death via the intrinsic apoptotic pathway. However, the documented strong cytotoxic off-target effects of 5-LO inhibitors, in combination with the relatively high concentrations of 5-LO products needed to achieve mitogenic effects in cell culture assays, raises concern over the assignment of the cause and question the relationship between 5-LO products and tumourigenesis.
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