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.
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DHA also inhibited the activity of NF-κB in PANC-1 cells. Fan et al.  reported that NF-κB and STAT3 signaling pathways collaborate in cancer cells via direct interaction and by cooperatively binding at a subset of gene promoters to synergistically induce their target genes. Through investigation, DHA was shown to inhibit the expression of the genes encoding cyclin D1 and survivin, both of which are regulated by STAT3 and NF-κB. In this sense, inhibition of STAT3 by DHA may influence NF-κB activation and thus suppress target genes in PANC-1 cells. We showed that DHA inhibited the phosphorylation of IκBα, which suppressed NF-κB activation. This finding is supported by previous work which showed that DHA pretreatment of hairless mouse skin attenuated ultraviolet (UV) B-induced DNA-binding of NF-κB through the inhibition of phosphorylation of IκB kinase-α/β, phosphorylation and degradation of IκBα, and nuclear translocation of p50 and p65 .
Funding: This research was partially funded by a Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea.
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All Science Journal Classification (ASJC) codes
- Food Science
- Nutrition and Dietetics