Regulatory mechanism of polyunsaturated fatty acid in pancreatic cancer development
Abstract: Pancreatic ductal adenocarcinoma (PDCA) is one of the most aggressive and lethal cancers in the western world with a very poor survival. A characteristic pathway in the initiation of PDAC is the activation of the lipid-modified Sonic Hedgehog (SHH) ligand. Polyunsaturated fa...
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| Formato: | Artículo revista |
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Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología
2021
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| Acceso en línea: | https://revistas.unc.edu.ar/index.php/med/article/view/35056 |
| Aporte de: |
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I10-R327-article-35056 |
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Universidad Nacional de Córdoba |
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I-10 |
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R-327 |
| container_title_str |
Revista de la Facultad de Ciencias Médicas de Córdoba |
| format |
Artículo revista |
| topic |
pancreatic ductal adenocarcinoma (PDAC) polyunsaturated fatty acids (PUFAs) Sonic Hedgehog (SHH) peroxisome proliferator-activated receptor gamma adenocarcinoma de páncreas ductal (ACPD) ácidos grasos poliinsaturados (AGPs) Sonic Hedgehog (SHH) Receptor Gama Activado por Proliferadores de Peroxisomas gama (PPARγ) |
| spellingShingle |
pancreatic ductal adenocarcinoma (PDAC) polyunsaturated fatty acids (PUFAs) Sonic Hedgehog (SHH) peroxisome proliferator-activated receptor gamma adenocarcinoma de páncreas ductal (ACPD) ácidos grasos poliinsaturados (AGPs) Sonic Hedgehog (SHH) Receptor Gama Activado por Proliferadores de Peroxisomas gama (PPARγ) Garay , MI Mazzo , T Ferrero , V Barotto , NN Fernandez Zapico , ME Pasqualini , ME Regulatory mechanism of polyunsaturated fatty acid in pancreatic cancer development |
| topic_facet |
pancreatic ductal adenocarcinoma (PDAC) polyunsaturated fatty acids (PUFAs) Sonic Hedgehog (SHH) peroxisome proliferator-activated receptor gamma adenocarcinoma de páncreas ductal (ACPD) ácidos grasos poliinsaturados (AGPs) Sonic Hedgehog (SHH) Receptor Gama Activado por Proliferadores de Peroxisomas gama (PPARγ) |
| author |
Garay , MI Mazzo , T Ferrero , V Barotto , NN Fernandez Zapico , ME Pasqualini , ME |
| author_facet |
Garay , MI Mazzo , T Ferrero , V Barotto , NN Fernandez Zapico , ME Pasqualini , ME |
| author_sort |
Garay , MI |
| title |
Regulatory mechanism of polyunsaturated fatty acid in pancreatic cancer development |
| title_short |
Regulatory mechanism of polyunsaturated fatty acid in pancreatic cancer development |
| title_full |
Regulatory mechanism of polyunsaturated fatty acid in pancreatic cancer development |
| title_fullStr |
Regulatory mechanism of polyunsaturated fatty acid in pancreatic cancer development |
| title_full_unstemmed |
Regulatory mechanism of polyunsaturated fatty acid in pancreatic cancer development |
| title_sort |
regulatory mechanism of polyunsaturated fatty acid in pancreatic cancer development |
| description |
Abstract:
Pancreatic ductal adenocarcinoma (PDCA) is one of the most aggressive and lethal cancers in the western world with a very poor survival. A characteristic pathway in the initiation of PDAC is the activation of the lipid-modified Sonic Hedgehog (SHH) ligand. Polyunsaturated fatty acids (PUFAs) are natural ligands of the transcription factor Gamma Peroxisome Proliferator Activated Receptor (PPARγ), which is also key to the SHH metabolic network. However, it is unknown how PUFAs regulate the SHH signaling pathway and PPARγ involved in the development of PDAC. Here we evaluated the effect of ω-3 and ω-6 PUFAs on SHH and PPARγ activation on tumor progression employing the human pancreatic cancer line PANC-1 in-vitro and in KPC knock-in transgenic mice in-vivo.
PANC-1 cells were treated with PUFAs: arachidonic acid (ω-6, AA), eicosapentaenoic acid (ω-3, EPA) or docosahexaenoic acid (ω-3, DHA). Animals were fed with a semisynthetic diet with corn oil (ω-6) or fish oil (ω-3). The mRNA was analyzed by qPCR, proteins by Western Blot and cell viability of PANC-1 by Resazurin. Gas Chromatography was used to analyze the PUFAs profile of the PANC-1 cells and KPC mice tumors. Tumor volume was measured using a caliper, the fibrotic index by histologic assessment (Masson staining) and SHH by Immunochemistry. Data were analyzed by ANOVA.
In PANC-1 cells the results showed that DHA reduced SHH gene and protein expression, increased PPARγ expression levels (p<0.05) and reduced cell viability in a dose-dependent manner (p<0.0001). Membrane lipid profile in PANC-1 and in KPC tumor cells correlated with pure and dietary PUFAs treatment respectively. The ω-3 significantly reduced tumor size (p<0.05), stromal desmoplasia (p<0.01) and SHH expression (p<0.05).
The data obtained demonstrate that ω-3 PUFAs could modulate pancreatic tumor progression through PPARγ activation and SHH regulation promoting changes in the tissue environment affecting tumor growth.
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| publisher |
Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología |
| publishDate |
2021 |
| url |
https://revistas.unc.edu.ar/index.php/med/article/view/35056 |
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I10-R327-article-350562024-04-15T16:19:09Z Regulatory mechanism of polyunsaturated fatty acid in pancreatic cancer development Mecanismo regulatorio del desarrollo de cáncer pancreático mediado por ácidos grasos poliinsaturados A Garay , MI Mazzo , T Ferrero , V Barotto , NN Fernandez Zapico , ME Pasqualini , ME pancreatic ductal adenocarcinoma (PDAC) polyunsaturated fatty acids (PUFAs) Sonic Hedgehog (SHH) peroxisome proliferator-activated receptor gamma adenocarcinoma de páncreas ductal (ACPD) ácidos grasos poliinsaturados (AGPs) Sonic Hedgehog (SHH) Receptor Gama Activado por Proliferadores de Peroxisomas gama (PPARγ) Abstract: Pancreatic ductal adenocarcinoma (PDCA) is one of the most aggressive and lethal cancers in the western world with a very poor survival. A characteristic pathway in the initiation of PDAC is the activation of the lipid-modified Sonic Hedgehog (SHH) ligand. Polyunsaturated fatty acids (PUFAs) are natural ligands of the transcription factor Gamma Peroxisome Proliferator Activated Receptor (PPARγ), which is also key to the SHH metabolic network. However, it is unknown how PUFAs regulate the SHH signaling pathway and PPARγ involved in the development of PDAC. Here we evaluated the effect of ω-3 and ω-6 PUFAs on SHH and PPARγ activation on tumor progression employing the human pancreatic cancer line PANC-1 in-vitro and in KPC knock-in transgenic mice in-vivo. PANC-1 cells were treated with PUFAs: arachidonic acid (ω-6, AA), eicosapentaenoic acid (ω-3, EPA) or docosahexaenoic acid (ω-3, DHA). Animals were fed with a semisynthetic diet with corn oil (ω-6) or fish oil (ω-3). The mRNA was analyzed by qPCR, proteins by Western Blot and cell viability of PANC-1 by Resazurin. Gas Chromatography was used to analyze the PUFAs profile of the PANC-1 cells and KPC mice tumors. Tumor volume was measured using a caliper, the fibrotic index by histologic assessment (Masson staining) and SHH by Immunochemistry. Data were analyzed by ANOVA. In PANC-1 cells the results showed that DHA reduced SHH gene and protein expression, increased PPARγ expression levels (p<0.05) and reduced cell viability in a dose-dependent manner (p<0.0001). Membrane lipid profile in PANC-1 and in KPC tumor cells correlated with pure and dietary PUFAs treatment respectively. The ω-3 significantly reduced tumor size (p<0.05), stromal desmoplasia (p<0.01) and SHH expression (p<0.05). The data obtained demonstrate that ω-3 PUFAs could modulate pancreatic tumor progression through PPARγ activation and SHH regulation promoting changes in the tissue environment affecting tumor growth. Resumen: El adenocarcinoma de páncreas ductal (ACPD) es uno de los cánceres más mortales entre todas las neoplasias del mundo occidental con escasa sobrevida. Una vía característica en la iniciación de ACPD es la activación del ligando Sonic Hedgehog (SHH), modificado por lipidos. Los ácidos grasos poliinsaturados (AGPs) también son ligandos naturales del factor de transcripción Receptor Gama Activado por Proliferadores de Peroxisomas gama (PPARγ) que además, es clave de la red metabólica de SHH. Sin embargo se desconoce como los AGPs regulan la vía de señalización de SHH y el factor PPARγ involucrados en el desarrollo del ACPD. Aquí evaluamos el efecto de AGPs ω-3 y ω-6 sobre la activación de SHH y PPARγ en la progresión tumoral empleando la línea de cáncer pancreático humano PANC-1 in-vitro y en ratones transgénicos knock-in KPC in-vivo. Las PANC-1 fueron tratadas con AGPs: ácido araquidónico (ω-6, AA), ácido eicosapentanoico (ω-3, EPA) o ácido docosahexaenoico (ω-3, DHA). Los animales fueron alimentados con una dieta semisintética con aceite de maíz (ω-6) o aceite de pescado (ω-3). Se analizó el ARNm por qPCR, las proteinas por Western Blot y la viabilidad en PANC-1 mediante Resazurina. Se analizaron los datos por ANOVA. En PANC-1 y en tumores de ratones KPC se evaluó el perfil de AGPs por cromatografía gaseosa. Se analizó el volumen tumoral usando calimetro, el índice fibrótico en cortes histológicos (tinción Masson) y SHH por Inmunohistoquimica. Los resultados indicaron que en PANC-1, el DHA redujo la expresión génica y proteica de SHH, incrementó los niveles de expresión de PPARγ (p<0.05) y redujo la viabilidad celular de manera dosis-dependiente (p<0.0001). El perfil lipídico de membranas en PANC-1 y células tumorales KPC se correlacionó con el tratamiento de AGPs puros y dietarios respectivamente. Los ω-3 redujeron significativamente el tamaño tumoral (p<0.0452), la desmoplasia estromal (p<0.0082) y la expresión de SHH (p<0.0433). Los datos obtenidos demuestran que los AGPs ω-3 podrían modular la progresión tumoral pancreática a través de la activación de PPARγ y de la regulación de SHH promoviendo cambios en el ambiente tisular afectando el crecimiento tumoral. . Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología 2021-10-12 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion texto texto texto https://revistas.unc.edu.ar/index.php/med/article/view/35056 Revista de la Facultad de Ciencias Médicas de Córdoba.; Vol. 78 No. Suplemento (2021): Suplemento JIC XXII Revista de la Facultad de Ciencias Médicas de Córdoba; Vol. 78 Núm. Suplemento (2021): Suplemento JIC XXII Revista da Faculdade de Ciências Médicas de Córdoba; v. 78 n. Suplemento (2021): Suplemento JIC XXII 1853-0605 0014-6722 http://creativecommons.org/licenses/by-nc/4.0 |