The nuclear eicosanoid receptor, PPARgamma, is aberrantly expressed in colonic cancers

DuBois, Raymond N.; Gupta, Rajnish A.; Brockman, Jeffrey A.; Reddy, Bandaru S.; Krakow, Samuel L.; Lazar, Mitchell A.

doi:10.1093/carcin/19.1.49

Cited by 234 publications

(152 citation statements)

References 36 publications

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“…Furthermore, increased expression of rabbit reticulocyte 15-LO is observed during reticulocyte maturation (51). The overexpression of peroxisome proliferator-activated receptor (PPAR)␥ in rat intestinal tumors was recently reported, and Caco-2 cells were found to express the highest levels of PPAR␥ of all the human colorectal cell lines tested (52). Furthermore, 13(S)-HODE and 9(S)-HODE bind to and activate the PPAR␥ (53).…”

Section: Discussionmentioning

confidence: 95%

Expression of 15-Lipoxygenase by Human Colorectal Carcinoma Caco-2 Cells during Apoptosis and Cell Differentiation

Kamitani

Geller

Eling

1998

Journal of Biological Chemistry

130

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We studied arachidonic acid metabolism and the expression of cyclooxygenase (Cox) and 15-lipoxygenase (15-LO) in the human colorectal carcinoma cell line, Caco-2, which undergo apoptosis and cell differentiation in the presence of sodium butyrate (NaBT). Caco-2 cells expressed very low levels of Cox-1 but highly expressed Cox-2. NaBT treatment shifted the arachidonic acid metabolites by cell lysates from prostaglandins to 15-hydroxyeicosatetraenoic acid, indicating the presence of a 15-LO. Linoleic acid, an excellent substrate for 15-LO, was metabolized poorly by the Caco-2 cells, but NaBT treatment shifted metabolism to 15-LO metabolite, 13(S)-hydroxyoctadecadienoic acid. Caco-2 cells expressed a 15-LO but only after treatment with NaBT, as determined by Northern blotting. Immunoblotting with anti-human 15-LO antibody detected a 72-kDa band in NaBT-treated Caco-2 cells. Expression of 15-LO mRNA was dependent on the duration of NaBT treatment, with the highest expression observed between 10 and 24 h. Results from expression and metabolism studies with arachidonic and linoleic acid cells indicated Cox-2 was responsible for the lipid metabolism in control cells, whereas 15-LO was the major enzyme responsible after NaBT induction of apoptosis and cell differentiation. The 15-LO in Caco-2 cells was characterized as human reticulocyte 15-LO by reverse transcription-polymerase chain reaction and restriction enzyme analysis. The expression of 15-LO and 15-hydroxyeicosatetraenoic acid or 13(S)-hydroxyoctadecadienoic acid formation correlates with cell differentiation or apoptosis in Caco-2 cells induced by NaBT. The addition of nordihydroguaiaretic acid, a lipoxygenase inhibitor, significantly increased NaBT-induced apoptosis, whereas the addition of indomethacin did not alter NaBT-induced apoptosis in the Caco-2 cells. However, indomethacin treatment decreased the expression of Cox-2 in NaBT-treated cells and significantly increased the expression of 15-LO during NaBT treatment. These studies suggest a role for 15-LO, in addition to Cox-2, in modulating NaBT-induced apoptosis and cell differentiation in human colorectal carcinoma cells.The first genetic alteration in the multistep process that leads to the development of colon carcinogenesis seems to be the loss of APC gene function. Investigations of APC function and its mutations have provided important clues in understanding colon cancer (1). One of the important changes that results from the loss of the APC gene function is the overexpression of prostaglandin H synthase-2 (cyclooxygenase-2, Cox-2), 1 an inducible enzyme that converts arachidonic acid to prostaglandins. The link between APC, Cox-2, and polyp formation was firmly established in studies using APC (Apc ⌬716 ) and Cox-2 knockout mice (2). Mice carrying the APC mutation overexpress Cox-2 and develop intestinal polyps. When bred to mice with the disrupted Cox-2 gene, the offspring, homozygously deficient for Cox-2, had significantly less polyps than the mice with wild-type Cox-2. These results confirmed C...

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Section: Discussionmentioning

confidence: 95%

Expression of 15-Lipoxygenase by Human Colorectal Carcinoma Caco-2 Cells during Apoptosis and Cell Differentiation

Kamitani

Geller

Eling

1998

Journal of Biological Chemistry

130

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“…These oxidation products are found in human plasma (42) and atherosclerotic lesions (43). PPAR␥, in contrast to PPAR␣, is aberrantly expressed in atherosclerotic lesions (20) and colonic tumors (44), which provide phospholipid oxidation products with the potential to alter the complement of genes expressed in such areas. Certain synthetic diacyl phospholipid oxidation products modestly activate PPAR␣ function (12).…”

Section: ϫ261mentioning

confidence: 99%

Oxidized Alkyl Phospholipids Are Specific, High Affinity Peroxisome Proliferator-activated Receptor γ Ligands and Agonists

Davies¹,

Pontsler²,

Marathe³

et al. 2001

Journal of Biological Chemistry

253

197

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Synthetic high affinity peroxisome proliferator-activated receptor (PPAR) agonists are known, but biologic ligands are of low affinity. Oxidized low density lipoprotein (oxLDL) is inflammatory and signals through PPARs. We showed, by phospholipase A 1 digestion, that PPAR␥ agonists in oxLDL arise from the small pool of alkyl phosphatidylcholines in LDL. We identified an abundant oxidatively fragmented alkyl phospholipid in oxLDL, hexadecyl azelaoyl phosphatidylcholine (azPC), as a high affinity ligand and agonist for PPAR␥. [ 3 H]azPC bound recombinant PPAR␥ with an affinity (K d(app) Ϸ40 nM) that was equivalent to rosiglitazone (BRL49653), and competition with rosiglitazone showed that binding occurred in the ligand-binding pocket. azPC induced PPRE reporter gene expression, as did rosiglitazone, with a half-maximal effect at 100 nM. Overexpression of PPAR␣ or PPAR␥ revealed that azPC was a specific PPAR␥ agonist. The scavenger receptor CD36 is encoded by a PPRE-responsive gene, and azPC enhanced expression of CD36 in primary human monocytes. We found that anti-CD36 inhibited azPC uptake, and it inhibited PPRE reporter induction. Results with a small molecule phospholipid flippase mimetic suggest azPC acts intracellularly and that cellular azPC accumulation was efficient. Thus, certain alkyl phospholipid oxidation products in oxLDL are specific, high affinity extracellular ligands and agonists for PPAR␥ that induce PPAR-responsive genes.The transcription factor PPAR␥, 1 in association with its 9-cis-retinoate-binding RXR partner, controls metabolic and cellular differentiation genes that contain variations of a cognate PPAR-response element (1). PPAR␥, like other members of the broad nuclear hormone receptor family, undergoes a conformational change when it binds specific lipid ligands. This structural reorganization alters its associated proteins, releasing transcriptional inhibitors and recruiting transcriptional co-activators. The regulation of PPAR␥ function is therefore controlled by lipid ligand binding.A number of synthetic ligands for PPAR␥ are known. One of these, rosiglitazone (BRL49653), binds with high affinity and is widely prescribed as an insulin sensitizer in type II diabetes. However, defining relevant biologic ligands has been problematic. Several oxidatively modified fatty acids bind and activate PPAR␥, including 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15-deoxy-PGJ 2 ), other arachidonate metabolites (2, 3), the linoleate derivatives 9-HODE and 13-HODE (4), and several free fatty acids (5, 6). However, none of these are particularly potent agonists, and for some their presence at concentrations sufficient to activate PPAR␥ can be questioned. For example, the oxygenated fatty acid products described above do not confer much advantage in potency over activation by free arachidonate (7) where a concentration of several micromolar is required to elicit a response. Moreover, the 9-and 13-HODEs and their peroxides found in oxidized LDL (8) or in skin exposed to the tumor promoter phorbol myristate ace...

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“…However, thus far, no functional difference has been found between the two isotypes. It has been established that human colorectal cells express only the PPAR␥1 isoform (9,27). From this point on, we will refer to PPAR␥1 as PPAR␥, since all of the subsequent experiments are done in HCT-116 human colorectal cells.…”

Section: Endogenous 15-lo-1 and Ppar␥ Expression In Hct-116mentioning

confidence: 99%

15-Lipoxygenase-1 Metabolites Down-regulate Peroxisome Proliferator-activated Receptor γ via the MAPK Signaling Pathway

Hsi

Wilson

Nixon

et al. 2001

Journal of Biological Chemistry

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The nuclear eicosanoid receptor, PPARgamma, is aberrantly expressed in colonic cancers

Cited by 234 publications

References 36 publications

Expression of 15-Lipoxygenase by Human Colorectal Carcinoma Caco-2 Cells during Apoptosis and Cell Differentiation

Expression of 15-Lipoxygenase by Human Colorectal Carcinoma Caco-2 Cells during Apoptosis and Cell Differentiation

Oxidized Alkyl Phospholipids Are Specific, High Affinity Peroxisome Proliferator-activated Receptor γ Ligands and Agonists

15-Lipoxygenase-1 Metabolites Down-regulate Peroxisome Proliferator-activated Receptor γ via the MAPK Signaling Pathway

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