Docoxahexaenoic Acid Induces Apoptosis of Pancreatic Cancer Cells by Suppressing Activation of STAT3 and NF-κB

Mirae Park,Hyeyoung Kim,Joo Lim

doi:10.3390/nu10111621

Abstract

The ω3-polyunsaturated fatty acid docosahexenoic acid (DHA) is known to induce apoptosis of cancer cells. In this study, DHA was shown to reduce viability of pancreatic cancer cells (PANC-1) by inducing DNA fragmentation, activating caspase-3, and increasing the ratio of Bax/Bcl-2. To determine the DHA mechanism of action, the impact of DHA on the activation of the key signaling proteins epidermal growth factor receptor (EGFR), signal transducer and activator of transcription factor 3 (STAT3), nuclear transcription factor-κB (NF-κB), and IκBα in PANC-1 cells was probed. The observed DHA suppression of NF-κB DNA-binding activity was found to result from reduced IκBα phosphorylation. The observed DHA-induced suppression of STAT3 activation was found to be the result of suppressed EGFR activation, which derives from the inhibitory effect of DHA on the integrity of localization of EGFR to cell membrane lipid rafts. Since the activation of STAT3 and NF-κB mediates the expression of survival genes cyclin D1 and survivin, DHA induced apoptosis by suppressing the STAT3/NF-κB-cyclin D1/survivin axis. These results support the proposal that DHA-induced apoptosis of pancreatic cells occurs via disruption of key pro-cell survival signaling pathways. We suggest that the consumption of DHA-enriched foods could decrease the incidence of pancreatic cancer.

Highlights

Pancreatic cancer is the eighth leading cause of cancer death in South Korea
To examine whether the decreased cell viability was due to the apoptotic effect of docosahexenoic acid (DHA), DNA fragmentation was probed by measuring the amount of nucleosome-bound DNA in DHA-treated vs. untreated cells
Caspase-3 exists as an inactive proenzyme, which is cleaved to the active enzyme in to apoptosis-inducing stimuli

Summary

Introduction

The five-year survival rate among pancreatic cancer patients is extremely low [1]. Because less than 20% of the cases are resectable, and the five-year survival rate after surgical resection is only 10–20% [2], a pressing need exists for the discovery of effective approaches to the treatment and prevention of pancreatic cancer. As is the case with many other malignancies, constitutively activated signal transducers and activators of transcription factor 3 (STAT3) play a key role in pancreatic cancer [3]. STAT3 undergoes dimerization, nuclear translocation, and binding to its target genes. The aberrant activation of STAT3 contributes to oncogenesis by preventing apoptosis through the up-regulation of target genes such as cyclin D1 and survivin [5,6]

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