REGULATORY MECHANISM OF POLYUNSATURATED FATTY ACID IN THE PANCREATIC CANCER DEVELOPMENT

GARAY ISABEL; MAZO TAMARA; FERRERO VICTORIA; BAROTTO NELSO N; BRUNOTTO MABEL; FERNANDEZ ZAPICO MARTIN; PASQUALINI MARIA EUGENIA

online

Congreso; Congreso SAIB-SAMIGE 2021; 2021

Sociedad argentina de investigación bioquímica y biología molecular

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), the number of metastasis was counted on histological sections dyed with H-E and apoptotic cells, SHH and PPARγ by TUNEL and Immunohistochemistry techniques respectively. 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), lung and liver metastasis (p<0.05) and SHH expression (p<0.05). On the other hand, ω-3 significantly increased the apoptotic tissue (p<0,0048) and PPARγ levels (p<0.05) on pancreatic tumor. 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.