Journal article
Overexpressing TNF-Alpha in Pancreatic Ductal Adenocarcinoma Cells and Fibroblasts Modifies Cell Survival and Reduces Fatty Acid Synthesis via Downregulation of Sterol Regulatory Element Binding Protein-1 and Activation of Acetyl CoA Carboxylase
Journal of gastrointestinal surgery, v 18(2), pp 257-268
01 Feb 2014
PMID: 24091913
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The effect of tumor necrosis factor-alpha (TNF-alpha) gene delivery has been suggested as a potentially useful therapeutic approach to improve the chemotherapeutic treatment of patients with pancreatic ductal adenocarcinoma (PDA), but the exact mechanism of its action is not clearly understood. In this study, we analyzed the expression profile of TNF-alpha in PDA tissue and explored its potential role in fatty acid synthase (FAS) regulation in PDA cells and in fibroblasts. Quantitative real-time polymerase chain reaction was used to examine the expression of TNF-alpha in PDA, matching adjacent tissues, and benign lesions. Logistic regression models with robust variance were used to analyze the gene expression levels, and Kaplan-Meier survival curves were generated. In vitro, we overexpressed the TNF-alpha gene in PDA cells and fibroblasts and analyzed its effect on cell survival, migration, and on members of the FAS signaling pathway. We also evaluated TNF-alpha effects on a panel of inflammation-, angiogenesis-, and metastasis-related markers. In the tumor tissue of PDA patients, compared with their matched adjacent tissue, expression levels of TNF-alpha were not statistically different and did not correlate with survival or any other examined clinicopathological features. Overexpression of TNF-alpha significantly (p < 0.05) reduced PDA and fibroblast cell migration. In PDA cells that highly overexpress TNF-alpha, this was associated with a significant reduction of FAS mRNA and protein expression levels and significant (p < 0.05) reduction of SREBP-1 and ACC mRNA. Reduction of FAS by TNF-alpha was inhibited when either SREBP-1 or ACC was knocked down by siRNA. PDA cells and fibroblasts that overexpress TNF-alpha displayed differential regulation of several inflammation-related markers and reduced levels of metastasis-related genes. Our data demonstrate a previously unknown multi-targeted involvement of TNF-alpha in PDA lipogenesis and inflammation and metastasis and suggest that intratumoral introduction of TNF-alpha may have the potential as a novel therapeutic approach in human PDA.
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Details
- Title
- Overexpressing TNF-Alpha in Pancreatic Ductal Adenocarcinoma Cells and Fibroblasts Modifies Cell Survival and Reduces Fatty Acid Synthesis via Downregulation of Sterol Regulatory Element Binding Protein-1 and Activation of Acetyl CoA Carboxylase
- Creators
- Mazhar Al-Zoubi - Thomas Jefferson UniversityGalina Chipitsyna - Thomas Jefferson UniversityShivam Saxena - Thomas Jefferson UniversityKonrad Sarosiek - Thomas Jefferson UniversityAnkit Gandhi - Thomas Jefferson UniversityChristopher Y. Kang - Thomas Jefferson UniversityDaniel Relles - Thomas Jefferson UniversityJocelyn AndrelSendecki - Thomas Jefferson UniversityTerry Hyslop - Thomas Jefferson UniversityCharles J. Yeo - Thomas Jefferson UniversityHwyda A. Arafat - Thomas Jefferson University
- Publication Details
- Journal of gastrointestinal surgery, v 18(2), pp 257-268
- Publisher
- Springer Nature
- Number of pages
- 12
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine
- Web of Science ID
- WOS:000331379100016
- Scopus ID
- 2-s2.0-84893220536
- Other Identifier
- 991022047281504721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Gastroenterology & Hepatology
- Surgery