Dr. Ron’s Research Review – January 24, 2018

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This week’s research review focuses on PPAR-gamma.

PPAR-gamma regulates fatty acid storage and glucose metabolism by activating genes that stimulate lipid uptake and adipogenesis by fat cells. Many diabetes drugs (the thiazolidinediones) activate PPARG as a means to lower glucose without increasing pancreatic insulin secretion.

Cancer

Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors. Three subtypes have been identified: PPAR alpha, PPAR beta, and PPAR gamma. Recently, it has been shown that they are involved in regulating the cell cycle and apoptosis in both normal and tumor cells. (Nunez-Anita, Cajero-Juarez et al. 2011)

Iodine and 6-iodolactone

I2-treated rats for four weeks exhibited a significant reduction in the incidence (62.5 vs. 100%) and size (0.87 +/- 0.98 vs 1.96 +/- 1.5 cm3) of mammary tumors. Tumors from I2-treated rats showed a decrease in PPAR type alpha, and significant induction of PPAR type gamma. (Aceves, Garcia-Solis et al. 2009)

Gamma- and Delta-Tocopherols

Dietary administration of 0.1%, 0.3%, or 0.5% mixed tocopherols suppressed mammary tumor growth by 38%, 50%, or 80%, respectively. Gamma- and delta-tocopherols, but not alpha-tocopherol, activated peroxisome proliferator activated receptor-gamma and antagonized estrogen action in breast cancer. (Lee, Ju et al. 2009)

Celiac Disease

PPAR signaling pathway and cancer-related proteins are involved in celiac disease-associated tissue damage. Downregulation of proteins involved in PPAR signaling and the modulation of several cancer-related proteins are associated with the highest CD histological score according to Oberhuber-Marsh classification.(Simula, Cannizzaro et al. 2010)

 

Dr. Ron


Articles

 

Antineoplastic effect of iodine in mammary cancer: participation of 6-iodolactone (6-IL) and peroxisome proliferator-activated receptors (PPAR)
            (Aceves, Garcia-Solis et al. 2009) Download
INTRODUCTION: Studies in mammary cancer demonstrated that moderately high concentrations of molecular iodine (I2) have a antiproliferative and apoptotic effect either in vivo as in vitro, however the cellular intermediated involved in these effects has not been elucidated. METHODS: Virgin Sprague-Dawley rats were treated with methyl-nitrosourea (MNU: single dose ip, 50 mg/Kg bw) and the participation of arachidonic acid (AA) and PPAR receptors in the antineoplasic effect of I2 where analyzed. RESULTS: I2-treated rats for four weeks exhibited a significant reduction in the incidence (62.5 vs. 100%) and size (0.87 +/- 0.98 vs 1.96 +/- 1.5 cm3) of mammary tumors. HPLC analysis showed that tumoral but not normal mammary tissue contained an elevated basal concentration of AA and significantly more AA-iodinated called 6-iodolactone (6-IL) after chronic I2 treatment. Tumors from I2-treated rats showed fewer cells positive to proliferating cell nuclear antigen, lower blood vessel density, as well as decreases in vascular endothelial growth factor, urokinase-type plasminogen activator, and PPAR type alpha (PPARalpha). These same tumors showed increases in the cell death markers, TUNEL-positive cells (p < 0.05) and the enzyme caspase-3 (trend), as well as significant induction of PPAR type gamma (PPARgamma). CONCLUSION: Together, these data demonstrate that the antineoplasic effect of iodine involves 6-IL formation and PPARgamma induction.

Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-gamma
            (Lee, Ju et al. 2009) Download
PURPOSE: Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of alpha-tocopherol (vitamin E) have been studied for decades, recent intervention studies with alpha-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of four isoforms, which are the alpha, beta, gamma, and delta variants, and recent attention is being given to other isoforms. In the present study, we investigated the inhibitory effect of a tocopherol mixture rich in gamma- and delta-tocopherols against mammary tumorigenesis. EXPERIMENTAL DESIGN: Female Sprague Dawley rats were treated with N-methyl-N-nitrosourea (NMU), and then fed diets containing 0.1%, 0.3%, or 0.5% mixed tocopherols rich in gamma- and delta-tocopherols for 9 weeks. Tumor burden and multiplicity were determined, and the levels of markers of inflammation, proliferation, and apoptosis were evaluated in the serum and in mammary tumors. The regulation of nuclear receptor signaling by tocopherols was studied in mammary tumors and in breast cancer cells. RESULTS: Dietary administration of 0.1%, 0.3%, or 0.5% mixed tocopherols suppressed mammary tumor growth by 38%, 50%, or 80%, respectively. Tumor multiplicity was also significantly reduced in all three mixed tocopherol groups. Mixed tocopherols increased the expression of p21, p27, caspase-3, and peroxisome proliferator activated receptor-gamma, and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that gamma- and delta-tocopherols, but not alpha-tocopherol, activated peroxisome proliferator activated receptor-gamma and antagonized estrogen action in breast cancer. CONCLUSION: The results suggest that gamma- and delta-tocopherols may be effective agents for the prevention of breast cancer.

Peroxisome proliferator-activated receptors: role of isoform gamma in the antineoplastic effect of iodine in mammary cancer
            (Nunez-Anita, Cajero-Juarez et al. 2011) Download
Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors. Three subtypes--PPAR alpha, PPAR beta, and PPAR gamma--have been identified and are differentially expressed in tissues. Originally, they were described as molecular regulators of lipid metabolism; recently, it has been shown that they are also involved in regulating the cell cycle and apoptosis in both normal and tumoral cells. In fact, some synthetic PPAR ligands are used to treat dyslipidemia, metabolic diseases, and type 2 diabetes. Here, we review the role of PPAR gamma (PPARgamma) in tumor initiation and progression, emphasizing the relationship between this isoform and the cellular and molecular mechanisms involved in the antineoplastic effect of iodine on mammary cancer.

PPAR signaling pathway and cancer-related proteins are involved in celiac disease-associated tissue damage
            (Simula, Cannizzaro et al. 2010) Download
Celiac disease (CD) is an immune-mediated disorder triggered by the ingestion of wheat gliadin and related proteins in genetically predisposed individuals. To find a proteomic CD diagnostic signature and to gain a better understanding of pathogenetic mechanisms associated with CD, we analyzed the intestinal mucosa proteome alterations using two dimensional difference gel electrophoresis (2D-DIGE) coupled with matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF ms) of CD patients with varying degrees of histological abnormalities defined by Marsh criteria and controls. Our results clearly evidenced the presence of two groups of patients: Group A, including controls and Marsh 0-I CD patients; and Group B, consisting of CD subjects with grade II-III Oberhuber-Marsh classification. Differentially expressed proteins were involved mainly in lipid, protein and sugar metabolism. Interestingly, in Group B, several downregulated proteins (FABP1, FABP2, APOC3, HMGCS2, ACADM and PEPCK) were implicated directly in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Moreover, Group B patients presented a deregulation of some proteins involved in apoptosis/survival pathways: phosphatidylethanolamine-binding protein 1 (PEBP1), Ras-related nuclear protein (Ran) and peroxiredoxin 4 (PRDX4). PEBP1 downregulation and RAN and PRDX4 upregulation were associated with more severe tissue damage. Likewise, IgMs were found strongly upregulated in Group B. In conclusion, our results indicate that a downregulation of proteins involved in PPAR signaling and the modulation of several cancer-related proteins are associated with the highest CD histological score according to Oberhuber-Marsh classification.

Effect of nutritional vitamin A deficiency on lipid metabolism in the rat heart: Its relation to PPAR gene expression
            (Vega, Anzulovich et al. 2009) Download
OBJECTIVE: We studied the effect of dietary vitamin A deprivation on lipid composition and mRNA expression of regulatory enzymes involved in rat heart energetic lipid metabolism and its relation to the expression of peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor (RXR) genes. METHODS: Male Wistar 21-d-old rats were fed for 3 mo with a vitamin A-free diet (vitamin A-deficient group) and the same diet plus 8 mg of retinol palmitate per kilogram of diet (control group). One group of deficient animals received the control diet 15 d before sacrifice (vitamin A-refed group). Heart ventricular and mitochondrial lipid contents were determined. Lipid synthesis was measured using radioactive precursors and acetyl-coenzyme A carboxylase and mitochondrial carnitine palmitoyltransferase-I (CPT-I) activities using radioactive substrates. Fatty acid composition of mitochondrial phospholipids was analyzed by gas-liquid chromatography. Heart expression of acetyl-coenzyme A carboxylase, CPT-I, PPAR-alpha, PPAR-beta, RXR-alpha, and RXR-beta was assessed by reverse transcriptase polymerase chain reaction, and CPT-I expression was also measured by real-time polymerase chain reaction. RESULTS: Vitamin A deficiency induced changes in heart ventricular lipid content and synthesis. Mitochondrial cardiolipin decreased and the proportion of phospholipids/saturated fatty acids increased. Heart activity and mRNA levels of CPT-I and expression of PPAR-alpha and PPAR-beta genes were enhanced, whereas acetyl-coenzyme A carboxylase activity diminished. Furthermore, vitamin A deficiency decreased heart mRNA levels of RXRs. Vitamin A refeeding reverted most of the observed changes. CONCLUSION: Lipid metabolism is significantly modified in hearts of vitamin A-deficient rats. Alteration of mitochondrial energetic processes by modifying the activity and gene expressions of the regulatory enzymes is associated with a high PPAR expression induced by vitamin A deprivation.


References

Aceves, C., P. Garcia-Solis, et al. (2009). "Antineoplastic effect of iodine in mammary cancer: participation of 6-iodolactone (6-IL) and peroxisome proliferator-activated receptors (PPAR)." Mol Cancer 8: 33 PMID: 19500378
Lee, H. J., J. Ju, et al. (2009). "Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-gamma." Clin Cancer Res 15(12): 4242-9 PMID: 19509159
Nunez-Anita, R. E., M. Cajero-Juarez, et al. (2011). "Peroxisome proliferator-activated receptors: role of isoform gamma in the antineoplastic effect of iodine in mammary cancer." Curr Cancer Drug Targets 11(7): 775-86 PMID: 21762085
Simula, M. P., R. Cannizzaro, et al. (2010). "PPAR signaling pathway and cancer-related proteins are involved in celiac disease-associated tissue damage." Mol Med 16(5-6): 199-209 PMID: 20454521
Vega, V. A., A. C. Anzulovich, et al. (2009). "Effect of nutritional vitamin A deficiency on lipid metabolism in the rat heart: Its relation to PPAR gene expression." Nutrition 25(7-8): 828-38 PMID: 19342198