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01.02.2014 | 2013 SSAT Plenary Presentation | Ausgabe 2/2014

Journal of Gastrointestinal Surgery 2/2014

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

Zeitschrift:
Journal of Gastrointestinal Surgery > Ausgabe 2/2014
Autoren:
Mazhar Al-Zoubi, Galina Chipitsyna, Shivam Saxena, Konrad Sarosiek, Ankit Gandhi, Christopher Y. Kang, Daniel Relles, Jocelyn AndrelSendecki, Terry Hyslop, Charles J. Yeo, Hwyda A. Arafat
Wichtige Hinweise
Presented as a plenary presentation at the 54th Annual Meeting of the Society for Surgery of the Alimentary Tract, 18–21 May 2013, Orlando, FL.

Discussion

Dr. Steven J. Hughes (Gainsville, FL): In this series, Dr. Arafat and her colleagues have nicely provided us with some data to suggest there is a relationship exists between TNF alpha production and fatty acid metabolism. It’s really kind of fun to see work where you are combining a pathway that has been extensively without me really understanding exactly how that pathway works well with some new data suggesting that tumor cell metabolism, not only of fatty acids but of glucose and pyruvate, may be an attractive therapeutic target in the near future. Like most good work, I think that your work actually leaves me with more questions than with answers.
I have a few questions for you.
First of all, what led you to focus on the fatty acid metabolism rather than on glucose or pyruvate metabolism? Do you have data in this model with respect to how these high levels of TNFL may impact the cells ability to metabolize glucose or pyruvate?
The second question I have is what promoter were you using in your virus? Is it a CMV promoter or was it actually something like an elastace promoter which may be actually organ specific? Do you have any data as to whether or not an organ specific promoter such as elastace would drive levels of TNFL for production to get you a similar effect?
A couple other questions: One is we know that the TNFL for receptor can actually induce apoptosis, but then the other question becomes if you’re impacting metabolic production of fatty acids or glucose what do you think the mechanism of the apoptosis that you observed or at least decreased ability might be in this model?

Closing Discussant

Dr. Hwyda A. Arafat: Thank you Dr. Hughes for the careful review of the manuscript. As you have seen from our studies, we have done extensive work on the downstream genes affected by TNF. Due to our previous work on fatty acid metabolism, we made it the focus of our study. We have no data on glucose or pyruvate metabolism.
To answer your second question, the empty vector purchased from GeneCopoeia contains CMV as a promoter. We do not have data on the levels of TNF if elastace promoter was to be used.
As for your third question, it is already established that lipogenesis is an integral processes in cancer cell proliferation, which occurs through stimulation of fatty acid synthase (FAS) enzyme and its downstream targets. Inhibition of FAS by pharmacological inhibitors or siRNA has been shown to induce cancer cell death due to its deprivation of the consistent supply of lipids and lipid precursors that are needed to fuel membrane production and lipid-based post-translational modification of proteins in proliferating cancer cells. We believe that TNF-alpha mechanism of action is multi-targeted through impacting PDA lipogenesis, inflammation, and metastasis.

Abstract

The effect of tumor necrosis factor-alpha (TNF-α) 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-α 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-α 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-α 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-α 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-α were not statistically different and did not correlate with survival or any other examined clinicopathological features. Overexpression of TNF-α significantly (p < 0.05) reduced PDA and fibroblast cell migration. In PDA cells that highly overexpress TNF-α, 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-α was inhibited when either SREBP-1 or ACC was knocked down by siRNA. PDA cells and fibroblasts that overexpress TNF-α 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-α in PDA lipogenesis and inflammation and metastasis and suggest that intratumoral introduction of TNF-α may have the potential as a novel therapeutic approach in human PDA.

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