[Frontiers in Bioscience 3, e81-88, June 8, 1998]

	[Frontiers in Bioscience 3, e81-88, June 8, 1998] Reprints PubMed CAVEAT LECTOR
	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 7. MECHANISMS INVOLVED IN LIPOXYGENASE PRODUCT MEDIATED BREAST CANCER DEVELOPMENT. There are several mechanisms by which lipoxygenase products may mediate cellular growth. They have been shown to lead to the activation of oncogenes such as c-fos and ras (29,47). HETEs can also activate protein kinase C directly (39,48,49) or indirectly by incorporating into membrane phospholipids which then generate HETE-containing diacylglycerol species to activate protein kinase C (50). 12-HETE can also mimic the protein kinase C activator and tumor promoter, phorbol myristate acetate, in enhancing tumor cell integrin expression and adhesion (51). Evidence also suggests that 12-HETE can lead to G-protein mediated activation of phospholipase C (52). Studies have also shown that LO products can modulate intracellular calcium levels (53). Furthermore, a receptor-mediated mechanism of action with high affinity binding sites for 12-HETE has also been demonstrated in certain cells (52,54,55). Activation of the leukocyte-type of 12-lipoxygenase may cause structural modification of membrane phospholipids since it can not only oxidize free fatty acids but also those esterified to phospholipids, unlike the platelet form of 12-lipoxygenase (56). LO products may also mediate cellular effects by the activation of key growth and stress related kinases which are signaling components of gene transcription (57). In vascular smooth muscle cells, lipoxygenase products of arachidonic acid (HETEs) and linoleic acid (HODEs) could directly activate mitogen activated protein kinases (MAPKs) (58,59). Furthermore, in the CHO-AT1a cells, LO inhibitors could attenuate AII-induced MAPK (ERK1/2) activity, and LO products could directly activate ERK1/2 (60). Very recent evidence in the CHO-AT1a cells suggests that LO products, such as 12-HETE, also directly activate another member of the MAPK family, the c-Jun aminoterminal kinase (JNK) and furthermore, LO inhibitors blocked AII-induced JNK activation. (61). LO metabolites have also been shown to mediate the growth promoting effects of EGF, and the mechanism appeared to involve regulation of the tyrosine kinase activity of the EGF receptor (62). Thus, arachidonic acid and its LO metabolites may mediate growth factor-induced activation of specific protein kinases and hence play a key role in the aberrant behavior of cancer cells.

[Frontiers in Bioscience 3, e81-88, June 8, 1998]
Reprints
PubMed
CAVEAT LECTOR

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

7. MECHANISMS INVOLVED IN LIPOXYGENASE PRODUCT MEDIATED BREAST CANCER DEVELOPMENT.

There are several mechanisms by which lipoxygenase products may mediate cellular growth. They have been shown to lead to the activation of oncogenes such as c-fos and ras (29,47). HETEs can also activate protein kinase C directly (39,48,49) or indirectly by incorporating into membrane phospholipids which then generate HETE-containing diacylglycerol species to activate protein kinase C (50). 12-HETE can also mimic the protein kinase C activator and tumor promoter, phorbol myristate acetate, in enhancing tumor cell integrin expression and adhesion (51). Evidence also suggests that 12-HETE can lead to G-protein mediated activation of phospholipase C (52). Studies have also shown that LO products can modulate intracellular calcium levels (53). Furthermore, a receptor-mediated mechanism of action with high affinity binding sites for 12-HETE has also been demonstrated in certain cells (52,54,55). Activation of the leukocyte-type of 12-lipoxygenase may cause structural modification of membrane phospholipids since it can not only oxidize free fatty acids but also those esterified to phospholipids, unlike the platelet form of 12-lipoxygenase (56).

LO products may also mediate cellular effects by the activation of key growth and stress related kinases which are signaling components of gene transcription (57). In vascular smooth muscle cells, lipoxygenase products of arachidonic acid (HETEs) and linoleic acid (HODEs) could directly activate mitogen activated protein kinases (MAPKs) (58,59). Furthermore, in the CHO-AT1a cells, LO inhibitors could attenuate AII-induced MAPK (ERK1/2) activity, and LO products could directly activate ERK1/2 (60). Very recent evidence in the CHO-AT1a cells suggests that LO products, such as 12-HETE, also directly activate another member of the MAPK family, the c-Jun aminoterminal kinase (JNK) and furthermore, LO inhibitors blocked AII-induced JNK activation. (61). LO metabolites have also been shown to mediate the growth promoting effects of EGF, and the mechanism appeared to involve regulation of the tyrosine kinase activity of the EGF receptor (62). Thus, arachidonic acid and its LO metabolites may mediate growth factor-induced activation of specific protein kinases and hence play a key role in the aberrant behavior of cancer cells.