Polyunsaturated fatty acids-induced ferroptosis suppresses pancreatic cancer growth

Despite recent advances in science and medical technology, pancreatic cancer remains
associated with high mortality rates due to aggressive growth and no early clinical sign as well
as the unique resistance to anti-cancer chemotherapy. Current numerous investigations have
suggested that ferroptosis, which is a programed cell death driven by lipid oxidation, is an
attractive therapeutic in different tumor types including pancreatic cancer. Here, we first
demonstrated that linoleic acid (LA) and α-linolenic acid (αLA) induced cell death with
necroptotic morphological change in MIA-Paca2 and Suit 2 cell lines. LA and αLA increased
lipid peroxidation and phosphorylation of RIP3 and MLKL in pancreatic cancers, which were
negated by ferroptosis inhibitor, ferrostatin-1, restoring back to BSA control levels. Similarly,
intraperitoneal administration of LA and αLA suppresses the growth of subcutaneously
transplanted Suit-2 cells and ameliorated the decreased survival rate of tumor bearing mice,
while co-administration of ferrostatin-1 with LA and αLA negated the anti-cancer effect. We also
demonstrated that LA and αLA partially showed ferroptotic effects on the gemcitabine-resistant-
PK cells, although its effect was exerted late compared to treatment on normal-PK cells. In
addition, the trial to validate the importance of double bonds in PUFAs in ferroptosis revealed
that AA and EPA had a marked effect of ferroptosis on pancreatic cancer cells, but DHA showed
mild suppression of cancer proliferation. Furthermore, treatment in other tumor cell lines
revealed different sensitivity of PUFA-induced ferroptosis; e.g., EPA induced a ferroptotic effect
on colorectal adenocarcinoma, but LA or αLA did not. Collectively, these data suggest that
PUFAs can have a potential to exert an anti-cancer effect via ferroptosis in both normal and
gemcitabine-resistant pancreatic cancer.