Lipoxygenase metabolism: roles in tumor progression and survival

Abstract

The metabolism of arachidonic acid through lipoxygenase pathways leads to the generation of various biologically active eicosanoids. The expression of these enzymes vary throughout the progression of various cancers, and thereby they have been shown to regulate aspects of tumor development. Substantial evidence supports a functional role for lipoxygenase-catalyzed arachidonic and linoleic acid metabolism in cancer development. Pharmacologic and natural inhibitors of lipoxygenases have been shown to suppress carcinogenesis and tumor growth in a number of experimental models. Signaling of hydro[peroxy]fatty acids following arachidonic or linoleic acid metabolism potentially effect diverse biological phenomenon regulating processes such as cell growth, cell survival, angiogenesis, cell invasion, metastatic potential and immunomodulation. However, the effects of distinct LOX isoforms differ considerably with respect to their effects on both the individual mechanisms described and the tumor being examined. 5-LOX and platelet type 12-LOX are generally considered pro-carcinogenic, with the role of 15-LOX-1 remaining controversial, while 15-LOX-2 suppresses carcinogenesis. In this review, we focus on the molecular mechanisms regulated by LOX metabolism in some of the major cancers. We discuss the effects of LOXs on tumor cell proliferation, their roles in cell cycle control and cell death induction, effects on angiogenesis, migration and the immune response, as well as the signal transduction pathways involved in these processes. Understanding the molecular mechanisms underlying the anti-tumor effect of specific, or general, LOX inhibitors may lead to the design of biologically and pharmacologically targeted therapeutic strategies inhibiting LOX isoforms and/or their biologically active metabolites, that may ultimately prove useful in the treatment of cancer, either alone or in combination with conventional therapies.

Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas

“…For example, it has been shown that LTB4, the major product of 5-LOX, is capable of recruiting and enhancing the activity of potential anti-tumor effector immune cells at the site of tumor development. However, other studies suggest that LOX products may prevent the anti-tumor immune response and thereby actively enhance tolerance to tumors (Pidgeon et al, 2007). Future studies will define which bioactive LOX products affect the responses of the immune system into elimination or tolerance of tumors.…”

“…Among the LOX family, the 5-LOX isoform has been shown to be involved in tumorigenesis, as its inhibition blocks proliferation of a wide variety of tumoral cells, including lymphoid and myeloid cancer cells (Pidgeon et al, 2007). We found that NPM-ALK( þ ) ALCLs overexpressed 5-LOX (Figure 4a), as already shown for other cancers (Pidgeon et al, 2007;Radmark et al, 2007). The NPM-ALK-dependent increase in 5-LOX required ALK activity in lymphoid cells (Supplementary Figure 1a).…”

“…The role of 5-and 12-LOX is fairly clear and procarcinogenic in the cell types studied (Fu¨rstenberger et al, 2006;Pidgeon et al, 2007). In the field of hematological malignancies, the general interest for ROS and their metabolizing enzymes has recently been increasing.…”

“…Pharmacological studies with LOX inhibitors in cancers are difficult to interpret, as there are few isotype-specific inhibitors. However, one proposed 5-LOX-selective inhibitor, used in asthma therapy, Zileuton, has proven useful in blocking several types of cancer in animal models, often in combination with another target, such as cyclooxygenase-2 (COX-2), as shown for colon cancer (Pidgeon et al, 2007). The BCR-ABL chimeric oncogene also induces free radical production during its oncogenic process.…”

Increased invasion of malignant gliomas after 15-LO-1 and HSV-tk/ganciclovir combination gene therapy

“…8 15-Lipoxygenase-1 (15-LO-1) is a multifunctional enzyme able to produce a vast number of metabolites with diverse bioactivities. 9 Its expression has been demonstrated to be significantly decreased in several cancers, including breast, bladder, colon, skin and lung carcinomas. 10 A recent report by Viita et al 11,12 demonstrated that 15-LO-1 is able to prevent vascular endothelial growth factor-A-induced neovascularisation in rabbit eyes and skeletal muscle.…”