Arachidonic acid suppresses growth of human lung tumor A549 cells through down-regulation of ALDH3A1 expression.

Expression of aldehyde dehydrogenase 3A1 (ALDH3A1) in certain normal and tumor cells is associated with protection against the growth inhibitory effect of reactive aldehydes generated during membrane lipid peroxidation. We found that human lung tumor (A549) cells, which express high levels of ALDH3A1 protein, were significantly less susceptible to the antiproliferative effects of 4-hydroxynonenal compared to human hepatoma HepG2 or SK-HEP-1 cells that lack ALDH3A1 expression. However, A549 cells became susceptible to lipid peroxidation products when they were treated with arachidonic acid. The growth suppression of A549 cells induced by arachidonic acid was associated with increased levels of lipid peroxidation and with reduced ALDH3A1 enzymatic activity, protein, and mRNA levels. Furthermore, arachidonic acid treatment of the A549 cells resulted in an increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma), whereas NF-kappaB binding activity was inhibited. Blocking PPARgamma using a selective antagonist, GW9662, prevented the arachidonic acid-mediated reduction of ALDH3A1 expression as well as the growth inhibition of A549 cells, suggesting the central role of PPARgamma in these phenomena. The increase in PPARgamma and the reduction in ALDH3A1 were also prevented by exposing cells to vitamin E concomitant with arachidonic acid treatment. In conclusion, our data show that the arachidonic acid-induced suppression of A549 cell growth is associated with increased lipid peroxidation and decreased ALDH3A1 expression, which may be due to activation of PPARgamma.

[1]  K. Takimoto,et al.  Structure of the 5' flanking region of class 3 aldehyde dehydrogenase in the rat. , 1994, Archives of biochemistry and biophysics.

[2]  K. Takimoto,et al.  Characterization of the rat Class 3 aldehyde dehydrogenase gene promoter. , 1996, Nucleic acids research.

[3]  V. Vasiliou,et al.  Tissue distribution of inducible aldehyde dehydrogenase activity in the rat after treatment with phenobarbital or methylcholanthrene. , 1989, Pharmacology & toxicology.

[4]  A. Townsend,et al.  Oxazaphosphorine-specific resistance in human MCF-7 breast carcinoma cell lines expressing transfected rat class 3 aldehyde dehydrogenase. , 1994, The Journal of biological chemistry.

[5]  R. Lindahl,et al.  Inhibition of class-3 aldehyde dehydrogenase and cell growth by restored lipid peroxidation in hepatoma cell lines. , 1999, Free radical biology & medicine.

[6]  G. Struhl,et al.  Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb , 1998, Nature.

[7]  V. Vasiliou,et al.  Role of Human Aldehyde Dehydrogenases in Endobiotic and Xenobiotic Metabolism , 2004, Drug metabolism reviews.

[8]  V. Keshamouni,et al.  PPAR-γ Activation Inhibits Angiogenesis by Blocking ELR+CXC Chemokine Production in Non-small Cell Lung Cancer , 2005 .

[9]  J. Davaille,et al.  15-deoxy-Delta 12,14-prostaglandin J2 induces apoptosis of human hepatic myofibroblasts. A pathway involving oxidative stress independently of peroxisome-proliferator-activated receptors. , 2001, The Journal of biological chemistry.

[10]  V. Vasiliou,et al.  Negative regulation of the murine cytosolic aldehyde dehydrogenase-3 (Aldh-3c) gene by functional CYP1A1 and CYP1A2 proteins. , 1992, Biochemical and biophysical research communications.

[11]  V. Vasiliou,et al.  Mouse cytosolic class 3 aldehyde dehydrogenase (Aldh3a1): gene structure and regulation of constitutive and dioxin-inducible expression. , 1999, Pharmacogenetics.

[12]  L. Sreerama,et al.  Class 1 and class 3 aldehyde dehydrogenase levels in the human tumor cell lines currently used by the National Cancer Institute to screen for potentially useful antitumor agents. , 1997, Advances in experimental medicine and biology.

[13]  L. Sreerama,et al.  Phenolic antioxidant-induced overexpression of class-3 aldehyde dehydrogenase and oxazaphosphorine-specific resistance. , 1995, Biochemical pharmacology.

[14]  G. Muzio,et al.  Mechanisms involved in growth inhibition induced by clofibrate in hepatoma cells. , 2003, Toxicology.

[15]  R. Lindahl,et al.  Increase in class 2 aldehyde dehydrogenase expression by arachidonic acid in rat hepatoma cells. , 2001, The Biochemical journal.

[16]  Vasilis Vasiliou,et al.  Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family , 2005, Human Genomics.

[17]  F. Duranti,et al.  Intracellular ionic variations in the apoptotic death of L cells by inhibitors of cell cycle progression. , 1995, Experimental cell research.

[18]  V. Vasiliou,et al.  Response of [Ah] battery genes to compounds that protect against menadione toxicity. , 1995, Biochemical pharmacology.

[19]  V. Vasiliou,et al.  Role of the Ah Receptor and the Dioxin‐Inducible [Ah] Gene Battery in Toxicity, Cancer, and Signal Transduction a , 1993, Annals of the New York Academy of Sciences.

[20]  F. Bozzo,et al.  An overview of the effect of linoleic and conjugated‐linoleic acids on the growth of several human tumor cell lines , 2004, International journal of cancer.

[21]  P. Fisher,et al.  Up-regulation of p21 Gene Expression by Peroxisome Proliferator-Activated Receptor γ in Human Lung Carcinoma Cells , 2004, Clinical Cancer Research.

[22]  B. Seed,et al.  PPAR-γ agonists inhibit production of monocyte inflammatory cytokines , 1998, Nature.

[23]  J. Auwerx,et al.  PPARgamma activators improve glucose homeostasis by stimulating fatty acid uptake in the adipocytes. , 1998, Atherosclerosis.

[24]  R. Lindahl,et al.  The same xenobiotic response element is required for constitutive and inducible expression of the mammalian aldehyde dehydrogenase-3 gene. , 1999, Archives of biochemistry and biophysics.

[25]  M. Lazar.  PPARγ, 10 years later , 2005 .

[26]  A. Azzi,et al.  4-hydroxy-2,3-trans-nonenal induces transcription and expression of aldose reductase. , 1996, Biochemical and biophysical research communications.

[27]  R. Haynes,et al.  Structure-activity relationships for growth inhibition and induction of apoptosis by 4-hydroxy-2-nonenal in raw 264.7 cells. , 2000, Molecular pharmacology.

[28]  D. Petersen,et al.  α,β-Unsaturated Aldehydes Increase GlutathioneS-Transferase mRNA and Protein: Correlation with Activation of the Antioxidant Response Element , 1998 .

[29]  J. Shelhamer,et al.  PPARγ ligands inhibit cholangiocarcinoma cell growth through p53‐dependent GADD45 and p21WAF1/Cip1 pathway , 2003, Hepatology.

[30]  R. Lindahl,et al.  Constitutive Expression of Class 3 Aldehyde Dehydrogenase in Cultured Rat Corneal Epithelium (*) , 1996, The Journal of Biological Chemistry.

[31]  G. Muzio,et al.  Inhibition of cytosolic class 3 aldehyde dehydrogenase by antisense oligonucleotides in rat hepatoma cells. , 2001, Chemico-biological interactions.

[32]  J. Kral,et al.  The NF-κB/IκB signaling system: A molecular target in breast cancer therapy , 2005 .

[33]  L. Harrison,et al.  Ciglitazone-induced cellular anti-proliferation increases p27kip1 protein levels through both increased transcriptional activity and inhibition of proteasome degradation. , 2005, Cellular signalling.

[34]  L. Harrison,et al.  Phosphorylation of PPARγ via active ERK1/2 leads to its physical association with p65 and inhibition of NF‐κβ , 2003 .

[35]  G. Muzio,et al.  Dose-dependent inhibition of cell proliferation induced by lipid peroxidation products in rat hepatoma cells after enrichment with arachidonic acid , 1999, Lipids.

[36]  L. Sreerama,et al.  Identification and characterization of a novel class 3 aldehyde dehydrogenase overexpressed in a human breast adenocarcinoma cell line exhibiting oxazaphosphorine-specific acquired resistance. , 1993, Biochemical pharmacology.

[37]  Y. Koutalos,et al.  Aldh3a1 protects human corneal epithelial cells from ultraviolet- and 4-hydroxy-2-nonenal-induced oxidative damage. , 2003, Free radical biology & medicine.

[38]  R. Lindahl,et al.  Aldehyde dehydrogenases and their role in carcinogenesis. , 1992, Critical reviews in biochemistry and molecular biology.

[39]  G. Poli,et al.  Physiological amounts of ascorbate potentiate phorbol ester-induced nuclear-binding of AP-1 transcription factor in cells of macrophagic lineage. , 2001, Free radical biology & medicine.

[40]  V. Vasiliou,et al.  Human aldehyde dehydrogenase 3A1 (ALDH3A1): biochemical characterization and immunohistochemical localization in the cornea. , 2003, The Biochemical journal.

[41]  A. Bairoch,et al.  Eukaryotic aldehyde dehydrogenase (ALDH) genes: human polymorphisms, and recommended nomenclature based on divergent evolution and chromosomal mapping. , 1999, Pharmacogenetics.

[42]  H P Koeffler,et al.  Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[43]  J. Piatigorsky.  Enigma of the Abundant Water-Soluble Cytoplasmic Proteins of the Cornea: The “Refracton” Hypothesis , 2001, Cornea.

[44]  Youngmi Kim Pak,et al.  Oxidized Low Density Lipoprotein Inhibits Interleukin-12 Production in Lipopolysaccharide-activated Mouse Macrophages via Direct Interactions between Peroxisome Proliferator-activated Receptor-γ and Nuclear Factor-κB* , 2000, The Journal of Biological Chemistry.

[45]  A. Bosio,et al.  Gene expression profiling in respiratory tissues from rats exposed to mainstream cigarette smoke. , 2003, Carcinogenesis.

[46]  B. Aggarwal,et al.  Nuclear factor-kappaB: the enemy within. , 2004, Cancer cell.

[47]  R. Lindahl,et al.  Enrichment with arachidonic acid increases the sensitivity of hepatoma cells to the cytotoxic effects of oxidative stress. , 1995, Free radical biology & medicine.

[48]  Y. Kadowaki,et al.  Can PPAR gamma ligands be used in cancer therapy? , 2004, Current medicinal chemistry. Anti-cancer agents.

[49]  U. Reichert,et al.  The effect of a novel irreversible inhibitor of aldehyde dehydrogenases 1 and 3 on tumour cell growth and death. , 2001, Chemico-biological interactions.

[50]  G. Poli,et al.  Role of aldehyde metabolizing enzymes in mediating effects of aldehyde products of lipid peroxidation in liver cells. , 1994, Carcinogenesis.

[51]  Aruni Bhatnagar,et al.  Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options. , 2005, Endocrine reviews.

[52]  Rajnish A. Gupta,et al.  Activation of PPARγ leads to inhibition of anchorage-independent growth of human colorectal cancer cells , 1998 .