12-lipoxygenase metabolite 12(S)-HETE stimulates human pancreatic cancer cell proliferationvia protein tyrosine phosphorylation and ERK activation

Abstract

We previously reported that inhibition of the 12-lipoxygenase pathway abolished proliferation and induced apoptosis in several pancreatic cancer cell lines. Furthermore, the 12-lipoxygenase product 12(S)-HETE stimulated pancreatic cancer cell proliferation and reversed 12-lipoxygenase inhibitorinduced growth inhibition. We investigated the underlying mechanism for 12(S)-HETE-induced pancreatic cancer cell proliferation, using 2 human pancreatic cancer cell lines, PANC-1 and HPAF. Cell proliferation was monitored by both thymidine incorporation and cell number. Key words: pancreatic cancer; mitogen-activated protein kinase; lipoxygenase; proliferation; 12(S)-HETEEpidemiologic and animal studies have linked pancreatic cancer growth with high fat intake, particularly unsaturated fats. 1-4 Concentration-dependent promotion of pancreatic cancer cell growth by linoleic acid has been demonstrated both in vivo and in vitro. 1,2,4 Furthermore, unsaturated fats in particular enhance carcinogen-induced pancreatic carcinogenesis in both hamsters and rats. [2][3][4] The 2 -6 polyunsaturated essential fatty acids, arachidonic and linoleic acid are substrates for 3 distinct enzymatic pathways: COX, LOX and epoxygenase. The LOX pathway catalyzes the incorporation of an oxygen molecule into polyunsaturated fatty acids containing the 1,4-cic,cis-pentadiene structure to yield a 1-hydroperoxy-2,4-trans,cis-pentadiene product. 5,6 Mammalian LOX possess regiospecificity for interaction with substrate and on that basis have been designated as arachidonate 5-, 12-and 15-LOX, which transiently produce 5(S)-, 12(S)-and 15(S)-HPETE and then 5(S)-, 12(S)-and 15(S)-HETE), respectively. 5,6 Several lines of evidence have shown the importance of LOX in regulating human cancer development and growth. [7][8][9][10][11][12] We previously reported that 12-LOX is expressed in several pancreatic cancer cell lines. 9 Blockade of 12-LOX markedly inhibits proliferation and induces apoptosis in human pancreatic cancer cells. 8,9 In contrast, the 12-LOX metabolite 12(S)-HETE directly stimulates pancreatic cancer cell proliferation. 8 The underlying mechanism by which 12(S)-HETE stimulates pancreatic cancer cell proliferation has not been investigated. The current study shows that 12(S)-HETE concentration-and time-dependently enhances pancreatic cancer cell proliferation by inducing tyrosine phosphorylation of multiple cellular proteins and activation of ERKs. Blockade of either tyrosine kinases or the MEK/ERK cascade inhibits the mitogenic effect of 12(S)-HETE. Furthermore, inhibition of tyrosine kinases blocked 12(S)-HETE-induced ERK phosphorylation, suggesting that cellular protein tyrosine phosphorylation is essential for 12(S)-HETE-induced ERK activation.

The Kaposi's Sarcoma-Associated Herpesvirus (KSHV)-Induced 5-Lipoxygenase-Leukotriene B4 Cascade Plays Key Roles in KSHV Latency, Monocyte Recruitment, and Lipogenesis

“…LTB4 mediates its actions by binding to two heterotrimeric G-protein-coupled seven-transmembrane receptors (GPCRs), LTB4R1 (BLT1R; a high-affinity receptor) and LTB4R2 (BLT2R; a low-affinity receptor) (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). LTB4 is a potent chemotactic mediator for granulocytes and T lymphocytes, plays critical functions in the immune system as a stimulator of monocytes and T and B lymphocytes, and allows ECs to promote transmigration, activation, and/or effector functions.…”

Up-regulation of 12(S)-lipoxygenase induces a migratory phenotype in colorectal cancer cells

“…12(S)-LOX (ALOX12) introduces a hydroxyl-group at position 12 of arachidonic acid to produce 12(S)-HETE [2,27], a mediator involved in tumour progression and metastasis in melanoma [28,29], prostate cancer [30], pancreatic cancer [31] as well as in angiogenesis in several tumour types reviewed in [32]. In prostate cancer 12(S)-LOX-over expression was correlated with advanced disease [13,33].…”

Targeting breast cancer cells by MRS1477, a positive allosteric modulator of TRPV1 channels

“…Endovanilloids are frequently produced in the “inflammatory soup”; anandamide, 12(S)-hydroxyeicosatetraenoic acid (12( S )-HETE), and other lipoxygenase metabolites of arachidonic and linoleic acids serve as potent agonists of TRPV1 [5,9,10]. These products are also present in the tumor microenvironment [11,12]. …”