ROLE OF LIPOXYGENASES IN BREAST CANCER

Rama Natarajan and Jerry Nadler

Department of Diabetes, Endocrinology and Metabolism¹, City of Hope National Medical Center, 1500, E. Duarte Road, Duarte, California 91010, USA.

Received 5/15/98 Accepted 5/29/98

3. ARACHIDONIC ACID METABOLISM AND THE LIPOXYGENASES

The interaction of growth factors and hormones with their cell surface receptors stimulates a cascade of signaling events including the activation of receptor tyrosine kinases, activation of several downstream signal transducing proteins and kinases and increased transcription of multiple genes. In addition, growth factor-induced activation of phospholipases can lead to the hydrolysis of membrane phospholipids, thereby releasing lipids such as arachidonic and linoleic acids. It has been suggested that the release of arachidonic acid from the sn-2 position of membrane phospholipids may be one of the signals leading to cellular proliferation (1). Arachidonic acid is also the precursor for several eicosanoids with potent biological effects including inflammation and cell growth (2 ). Arachidonic acid or one of its biologically active eicosanoid metabolites may play a role in cellular growth and inflammation.

The 20-carbon arachidonic acid can be metabolized by three major pathways, the cyclooxygenase pathway which leads to the formation of prostaglandins, the lipoxygenase (LO) pathway which forms hydroperoxyeicosatetraenoic acids (HPETEs), hydroxyeicosatetraenoic acids (HETEs) and leukotrienes and thirdly, the cytochrome P-450 monooxygenase pathway which leads to the formation of epoxides such as epoxyeicosatrienoic acids as well as HETEs (3) (figure 1). The lipoxygenases, mainly called 5-, 12- and 15-lipoxygenases (LOs) are named for their ability to insert molecular oxygen at the 5, 12, or 15 carbon atom of arachidonic acid (4). The 5-lipoxygenase pathway leads to the formation of 5-HETE and leukotrienes while the 12- and 15-lipoxygenases can form 12- and 15-HETEs.

Figure 1. Arachidonic acid metabolism.

Studies show that there are at least two major isoforms of 12-LOs (5-7). The platelet-type has been cloned from human platelets and the megakaryocytic cell line, HEL (8,9). The other 12-LO, namely the leukocyte-type, has been detected in porcine leukocytes (10), pituitary (11), vascular smooth muscle cells (12) and also in human adrenal glomerulosa cells (13), human monocytes, endothelial and vascular smooth muscle cells (14). The cDNA for porcine leukocyte 12-lipoxygenase has been cloned (10). This porcine leukocyte 12-lipoxygenase is only 65% homologous to the human platelet 12-lipoxygenase (8-10) whereas it is 87% homologous to human 15-lipoxygenase (10,15). A bovine-trachea epithelial-cell 12-lipoxygenase cDNA has also been cloned which is 86% identical to the human 15-lipoxygenase and 89% identical to the porcine 12-lipoxygenase (16). The two distinct 12-lipoxygenase cDNAs, namely platelet- and leukocyte-type, have recently been cloned from the same species, namely the mouse (17). 15-lipoxygenase has been cloned from human reticulocytes (15). Platelet 12-LO differs from leukocyte 12-LO in substrate specificity. The former is much less active with C18 fatty acids such as linoleic acid in comparison with arachidonic acid while leukocyte 12-LO has broader substrate specificity reacting with C18 and C22 unsaturated fatty acids as efficiently as with arachidonic acid (5).