13-hydroxy-9-11-octadecadienoic-acid and Lung-Neoplasms

Pioglitazone (PGZ), a synthetic peroxisome proliferator-activated receptor gamma (PPARγ) ligand, is known to have anti-tumor activity by inducing tumor cell apoptosis. However, it is unknown whether it can be used to prevent smoking carcinogen-induced lung tumor development. We induced mouse lung tumors using smoking carcinogen 4- methylnitrosamino-l-3-pyridyl-butanone (NNK). PGZ was given at two early stages before the tumor formation. The role and the functional mechanism of PGZ were investigated in the development of mouse pulmonary tumors. The tumor development was monitored and PPARγ activity and endogenous PPARγ ligands 15(S)-HETE, 13(S)-HODE were determined. The application of PGZ before alveolar hyperplasia formation (Group NPa) and at the early phase of alveolar hyperplasia formation (Group NPb) significantly prevented the lung tumor development especially in Group NPb mice (all p < 0.05). PGZ not only prevented the NNK-mediated reduction of endogenous ligands 15(S)-HETE and 13(S)-HODE, but also increased 13(S)-HODE level in Group NPb mice. PPARγ transcriptional activity was increased in NNKstimulated lung tissues when PGZ was given. The in vivo results were confirmed in the human lung cancer cells, which showed that PGZ induced lung cancer cell apoptosis through up-regulating nuclear PPARγ expression, inducing PPARγ transcriptional activity and increasing the levels of PPARγ ligands in NNK-treated cells. The early application of PGZ is able to prevent NNK-induced lung tumor development through maintaining the level of endogenous PPARγ ligands 15(S)-HETE and 13(S)-HODE and activation of PPARγ.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Humans; Hydroxyeicosatetraenoic Acids; Hyperplasia; Ligands; Linoleic Acids; Lung Neoplasms; Mice; Nitrosamines; Pioglitazone; PPAR gamma; Pulmonary Alveoli; Smoking; Thiazolidinediones; Time Factors; Transcription, Genetic

Peroxisome proliferator-activated receptor (PPAR)-α and PPARγ participate in cell proliferation and apoptosis. Few studies have simultaneously investigated both PPARα and PPARγ in lung cancers in vivo. The roles of PPARα and -γ were investigated in the development of pulmonary tumors induced in the adult A/J mouse by treatment with 4-(methylnitrosamino)-l-(3-pyridyl)-lbutanone (NNK). Compared with the normal lung tissues, PPARγ expression was much higher in the NNK-induced lung tumor tissues. However, PPARγ transcriptional activity, and the levels of two major endogenous PPARγ ligands, 13-hydroxyoctadecadienoic acid and 15-hydroxyeicosatetraenoic acid, were significantly lower in the NNK-treated lung tissues. The ligand changes in mice were confirmed in human lung cancer tissues. Along with the alteration of PPARγ and its endogenous ligands, the level of PPARα and its activity were increased in the NNK-induced mouse lung tumors. Treatment of mice with the synthetic PPARγ ligand, pioglitazone, significantly inhibited the formation of mouse lung tumors induced by NNK. Our study demonstrated that the reduction of endogenous PPARγ ligands and increased PPARα occurred before the formation of lung tumors, indicating that the molecular changes play a role in lung carcinogenesis. The results suggest that the enhancement of PPARγ activity with its ligands, and the suppression of PPARα with its inhibitors, may prevent the formation of lung tumors, as well as accelerate the therapy of lung cancer. Our findings may also reveal the possibility of using the level of endogenous PPARγ ligands and the activities of PPARγ or PPARα as tumor markers for lung cancer.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Humans; Hydroxyeicosatetraenoic Acids; Ligands; Linoleic Acids; Lipid Metabolism; Lung Neoplasms; Male; Mice; Nitrosamines; Pioglitazone; PPAR alpha; PPAR gamma; Precancerous Conditions; Retinoid X Receptor alpha; Signal Transduction; Thiazolidinediones; Transcription, Genetic

15-S-Hydroxyeicosatetraenoic acid (15(S)-HETE) and 13-S-hydroxyoctadecadienoic acid (13(S)-HODE), both of which are metabolites of 15-lipoxygenases (15-LOXs), are endogenous ligands for peroxisome proliferator-activated receptor gamma (PPARgamma). The activation of PPARgamma inhibits cell growth and induces apoptosis in some cancers. The role of 15(S)-HETE) and 13(S)-HODE in the development of lung cancer is not clear.. 15-LOXs, 15(S)-HETE and 13(S)-HODE were monitored during the development of mouse lung tumours induced by the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and the levels of these markers were determined in 54 human non-small cell lung cancers.. 15-LOXs, 15(S)-HETE and 13(S)-HODE levels were significantly reduced in human lung cancer tissue compared with non-tumour lung tissue (p=0.011 and p=0.022, respectively). In mouse experiments, 15(S)-HETE and 13(S)-HODE started to reduce at 26 and 30 weeks, respectively, after NNK treatment. The time frame of 15(S)-HETE reduction was in line with the decrease in 12/15-LOX mRNA and protein. A significant difference in the number of tumours in NNK-treated mice and controls was not observed until week 34 (p<0.05) and week 38 (p<0.01). The reduction in 12/15-LOX and 15(S)-HETE therefore predated the appearance of lung tumour. Furthermore, PPARgamma activity was decreased in NNK-treated mouse lungs compared with the control, and the decreased PPARgamma activity occurred at the same time points as the reduction in 12/15-LOX and 15(S)-HETE.. These findings indicate that the reduction in 15-LOX, 15(S)-HETE and 13(S)-HODE results in the decreased PPARgamma activity seen in lung tumours and contributes to the development of lung tumours induced by tobacco smoking.

Topics: Animals; Arachidonate 15-Lipoxygenase; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Cell Transformation, Neoplastic; Disease Models, Animal; Disease Progression; Female; Humans; Hydroxyeicosatetraenoic Acids; Linoleic Acids; Lung; Lung Neoplasms; Mice; Mice, Inbred A; Neoplasm Proteins; Nitrosamines; PPAR gamma

The arachidonate 15-lipoxygenase is induced in peripheral human monocytes by culturing the cells for 3 days in the presence of interleukin 4 (IL-4) in concentrations as low as 40 pM. Linoleic acid is oxygenated by IL-4 treated monocytes to 13(S)-hydroxy-9Z, 11E-octadecadienoic acid [13(S)-HODE] with a specific activity of about 2 nmoles 13(S)-HODE/10(6) cells min. A screening of various permanent cell lines expressing the IL-4 receptor indicated that all monocyte/macrophage lines tested did not exhibit the effect of LOX induction. However, IL-4 treatment of the lung carcinoma cell line CCC 185 and of the colon carcinoma cell line HTB 38 induces the 15-LOX as shown by activity assay and immunohistochemistry. The IL-4 mutant Y124D which has been characterized as specific IL-4 receptor antagonist in human T-cells does not induce the 15-LOX but appears to act as competitive inhibitor for the induction. Subcellular fractionation of IL-4 treated monocytes indicated a cytosolic and a membrane bound enzyme pool. The intracellular action of the LOX leads to a specific oxygenation of the membrane phospholipids which is drastically increased after damage to the cells. The possible biological role of the 15-LOX for monocyte metabolism is discussed.

Topics: Arachidonate 15-Lipoxygenase; Cells, Cultured; Colonic Neoplasms; Cytokines; Enzyme Induction; HL-60 Cells; Humans; Interleukin-4; Linoleic Acids; Lung Neoplasms; Lymphocytes; Monocytes; Point Mutation; T-Lymphocytes; Tumor Cells, Cultured

Previously, we have demonstrated that stimulation of endothelial cells (ECs) with interleukin-1 alpha (IL-1 alpha) enhances the synthesis and expression of the vitronectin receptor (VnR), promotes VnR-dependent adhesion of human A549 adenocarcinoma cells to ECs, and is associated with decreased EC 13-hydroxyoctadecadienoic acid (13-HODE) synthesis in vitro. To determine whether these observations are relevant in vivo, we examined the acute retention and subsequent metastasis of intravenously-injected B16F10 melanoma cells in murine lungs, in relation to vessel wall 13-HODE. In C57BL/6 mice pretreated with IL-1 alpha, vessel wall 13-HODE was decreased and B16F10 lung entrapment and metastasis were increased. The latter two events were blocked by pretreating the animals with the GRGDS peptide. These data suggest a relationship between vessel wall 13-HODE synthesis, adhesion molecule expression, and adhesion of B16F10 cells to the endothelium.

Topics: Animals; Cell Adhesion; Down-Regulation; Endothelium, Vascular; Interleukin-1; Linoleic Acids; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Oligopeptides; Receptors, Cytoadhesin; Receptors, Vitronectin; Recombinant Proteins

Lewis lung carcinoma cells express a plasma membrane receptor (i.e., IRGpIIb/IIIa) which is immunologically and functionally related to the platelet aggregation receptor complex (i.e., GpIIb/IIIa). Both fluorescence microscopy and flow cytometric analysis reveal that surface expression and/or activation of this tumor cell receptor is enhanced by a phorbol ester [i.e., 12-O-tetradecanoylphorbol-13-acetate (TPA)] and a lipoxygenase metabolite of arachidonic acid; 12-hydroxyeicosatetraenoic acid (i.e., 12-HETE). TPA-enhanced expression appears to be mediated by a lipoxygenase metabolite, as this effect can be reversed by lipoxygenase inhibitors but not by cyclooxygenase inhibitors. In parallel with these results both TPA and 12(S)-HETE [but not 12(R)-HETE] enhance tumor cell adhesion to endothelial cells, subendothelial matrix and fibronectin, but not to type IV collagen. TPA-enhanced adhesion can be reduced by lipoxygenase inhibitors but not by cyclooxygenase inhibitors and in addition, stimulated adhesion can be blocked by pretreatment of tumor cells with specific polyclonal or monoclonal antibodies which react against IRGpIIb/IIIa. 12(S)-HETE-enhanced adhesion can also be inhibited by these same antibodies. In contrast, a lipoxygenase product of linoleic acid, 13(S)-hydroxyoctadecadienoic acid, inhibited TPA and 12(S)-HETE-enhanced tumor cell adhesion to endothelial cells, subendothelial matrix, and fibronectin. These results suggest that (a) IRGpIIb/IIIa is a multifunctional receptor which mediates tumor cell adhesion to a variety of biological substrata, (b) TPA enhances surface expression and/or activation of this receptor possibly via a lipoxygenase metabolite of arachidonic acid, and (c) these effects are opposed by a lipoxygenase metabolite of linoleic acid.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Antibodies; Antibodies, Monoclonal; Antigen-Antibody Complex; Arachidonic Acids; Cell Adhesion; Cell Membrane; Collagen; Endothelium, Vascular; Flow Cytometry; Fluorescent Antibody Technique; Hydroxyeicosatetraenoic Acids; Isomerism; Linoleic Acid; Linoleic Acids; Lipoxygenase; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Platelet Membrane Glycoproteins; Rats; Rats, Inbred Strains; Tetradecanoylphorbol Acetate