The treatment of
cancer cells obtained by blocking cellular metabolism has received a lot of attention recently. Previous studies have demonstrated that Kras mutation-mediated abnormal
glucose metabolism would lead to an aberrant cell proliferation in human pancreatic ductal
adenocarcinoma (PDAC) cells. Previous literature has suggested that consumption of
fish oil is associated with lower risk of
pancreatic cancer. In this study, we investigated the anti-
cancer effects of
docosahexaenoic acid (DHA) in human PDAC cells in vitro and in vivo. Omega-3
polyunsaturated fatty acids (PUFAs) such as DHA and
eicosapentaenoic acid (EPA) significantly inhibited the proliferation of human PDAC cells. The actions of DHA were evaluated through an induction of cell cycle arrest at G1 phase and noticed a decreased expression of
cyclin A,
cyclin E and
cyclin B proteins in HPAF-II cells. Moreover, it was found that co-treatment of DHA and
gemcitabine (GEM) effectively induced oxidative stress and cell death in HPAF-II cells. Interestingly, DHA leads to an increased oxidative
glutathione /reduced glutathione (
GSSG/GSH) ratio and induced cell apoptosis in HPAF-II cells. The findings in the study showed that supplementation of GSH or N-Acetyl
Cysteine (NAC) could reverse DHA-mediated cell death in HPAF-II cells. Additionally, DHA significantly increased cellular level of
cysteine, cellular
NADP/
NADPH ratio and the expression of
cystathionase (CTH) and SLCA11/xCT
antiporter proteins in HPAF-II cells. The action of DHA was, in part, associated with the inactivation of STAT3 cascade in HPAF-II cells. Treatment with xCT inhibitors, such as
erastin or
sulfasalazine (SSZ), inhibited the cell survival ability in DHA-treated HPAF-II cells. DHA also inhibited
nucleotide synthesis in HPAF-II cells. It was demonstrated in a mouse-xenograft model that consumption of
fish oil significantly inhibited the growth of pancreatic
adenocarcinoma and decreased cellular
nucleotide level in
tumor tissues. Furthermore,
fish oil consumption induced an increment of
GSSG/GSH ratio, an upregulation of xCT and CTH
proteins in
tumor tissues. In conclusion, DHA significantly inhibited survival of PDAC cells both in vitro and in vivo through its recently identified novel mode of action, including an increment in the ratio of
GSSG/GSH and
NADP/
NADPH respectively, and promoting reduction in the levels of
nucleotide synthesis.