Differential cell growth/apoptosis behavior of 13-hydroxyoctadecadienoic acid enantiomers in a colorectal cancer cell line

Abstract

Cyclooxygenases (COXs) and lipoxygenases (LOXs) are important enzymes that metabolize arachidonic and linoleic acids. Various metabolites generated by the arachidonic acid cascade regulate cell proliferation, apoptosis, differentiation, and senescence. Hydroxyoctadecadienoic acids (HODEs) are synthesized from linoleic acid, giving two enantiomeric forms for each metabolite. The aim was to investigate the effect of 13-HODE enantiomers on nondifferentiated Caco-2 cell growth/apoptosis. Our results indicate that 13(S)-HODE decreases cell growth and DNA synthesis of nondifferentiated Caco-2 cells cultured with 10% fetal bovine serum (FBS). Moreover, 13(S)-HODE showed an apoptotic effect that was reduced in the presence of a specific peroxisome proliferator-activated receptor-γ (PPARγ) antagonist. In addition, we observed that 13(S)-HODE but not 13(R)-HODE is a ligand to PPARγ, confirming the implication of this nuclear receptor in 13(S)-HODE actions. In contrast, 13(R)-HODE increases cell growth and DNA synthesis in the absence of FBS. 13(R)-HODE interaction with BLT receptors activates ERK and CREB signaling pathways, as well as PGE2 synthesis. These results suggest that the proliferative effect of 13(R)-HODE could be due, at least in part, to COX pathway activation. Thus both enantiomers use different receptors and have contrary effects. We also found these differential effects of 9-HODE enantiomers on cell growth/apoptosis. Therefore, the balance between (R)-HODEs and (S)-HODEs in the intestinal epithelium could be important to its cell growth/apoptosis homeostasis.

Role of Oxidized Lipids in Pulmonary Arterial Hypertension

“…141 Recently, it was demonstrated that the production of 9-/13-HODEs by nonenzymatic pathways leads to monocyte/ macrophage activation and inflammation in atherosclerosis disease. 141 In addition to an enhancement of inflammation arising from oxidative stress in PAH, downregulation of PPARγ in PAH impairs the anti-inflammatory effect of oxidized lipids. Nonetheless, more studies are required to fully understand the precise role of HODEs in PAH pathophysiology with respect to inflammation.…”

A proteomic analysis of acute leukemia cells treated with 9-hydroxyoctadecadienoic acid

“…It is reported that HODs showed more potent anti-tumor activities than lead compound CLA, especially (S)-HOD had more activity compared with the corresponding (R)-HOD [11, 13]. To date, the mechanism of 9-HOD involved of inhibiting cell proliferation and inducing apoptosis.…”

“…Hampel et al [10] indicated that 9- and 13-HODE, as endogenous fatty acid ligands for PPARγ, possess differential, ligand specific actions in monocytic cells to regulate cell cycle progression, apoptosis and PPARγ2 gene expression. Interesting, recent studies show that (S)-HODE decrease cell growth and DNA synthesis, and induce apoptosis of Caco-2 cells, whereas (R)-HODE presents the opposite action [11]. Therefore, the present study considered whether 9S-HOD affects acute leukemia HL-60 cells, and what is the mechanism?…”

Effect of extra virgin olive oil components on the arachidonic acid cascade, colorectal cancer and colon cancer cell proliferation

“…Targeted deletion of the EP 1 receptor of PGE 2 reduced the number of colonic lesions in APC min -induced polyp formation that was also reduced by a specific EP 1 antagonist (Watanabe et al, 1999), whereas EP 4 deletion reduced the tumor size. Considering all of this together, we have a complete picture of the main elements involved in the effects of the AA cascade on epithelial cell growth in physiological and patho-physiological conditions: AA is released by PLA 2 , then it is metabolized by COX-1/COX-2 to produce bioactive eicosanoids such as PGE 2 , which interact with specific receptors (EP 1 and EP 4 ) and activate cell signaling pathways involved in the control of intestinal epithelial cell growth (Sanchez and Moreno, 2002;Cabral et al, 2013;Cabral et al, 2014). Cianchi et al (2006) reported that the two major metabolic pathways of the AA cascade, COX and 5-LOX, are simultaneously up-regulated in CRC.…”

“…A high expression of the BLT 1 receptor of LTB 4 (Ihara et al, 2007) and the CystLT 1 receptor of LTD 4 was detected in human colon cancer tissues, whereas CysLT 2 receptor expression was reduced in colon cancer and was associated with poor prognosis, due to its capacity to induce differentiation and growth inhibition (Magnusson et al, 2007). Recently, we observed that several LOX metabolites from AA and linoleic acid such as LTB 4 , LTD 4 , 5-HETE, 12-HETE, 15-HETE and 13-hydroxyoctadecanoic acid are involved in the control of CRC cell line proliferation (Cabral et al, 2013;Cabral et al, 2014;Martín-Venegas et al, 2014;Cabral et al, 2015).…”