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Article

Eicosapentaenoic Acid Inhibits KRAS Mutant Pancreatic Cancer Cell Growth by Suppressing Hepassocin Expression and STAT3 Phosphorylation

1
Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei 11031, Taiwan
2
TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
3
Nutrition Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
4
Department of Obstetrics and Gynecology, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan
5
School of Nutrition and Health Sciences, Taipei Medical University, Taipei 11031, Taiwan
6
Diet and Nutrition Department, Shuang Ho Hospital, Taipei Medical University, New Taipei 23561, Taiwan
*
Authors to whom correspondence should be addressed.
Both authors shared the equal contribution to this work.
Academic Editors: George Kokotos and Sasanka Ramanadham
Biomolecules 2021, 11(3), 370; https://doi.org/10.3390/biom11030370
Received: 10 January 2021 / Revised: 12 February 2021 / Accepted: 24 February 2021 / Published: 2 March 2021
(This article belongs to the Collection Bioactive Lipids in Inflammation, Diabetes and Cancer)
Background: The oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation was reported to be the signature genetic event in most cases of pancreatic ductal adenocarcinoma (PDAC). Hepassocin (HPS/FGL1) is involved in regulating lipid metabolism and the progression of several cancer types; however, the underlying mechanism of HPS/FGL1 in the KRAS mutant PDAC cells undergoing eicosapentaenoic acid (EPA) treatment remains unclear. Methods: We measured HPS/FGL1 protein expressions in a human pancreatic ductal epithelial (HPNE) normal pancreas cell line, a KRAS-wild-type PDAC cell line (BxPC-3), and KRAS-mutant PDAC cell lines (PANC-1, MIA PaCa-2, and SUIT-2) by Western blot methods. HEK293T cells were transiently transfected with corresponding KRAS-expressing plasmids to examine the level of HPS expression with KRAS activation. We knocked-down HPS/FGL1 using lentiviral vectors in SUIT-2 cells and measured the cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clonogenicity assays. Furthermore, a lipidomic analysis was performed to profile changes in lipid metabolism after HPS/FGL1 knockdown. Results: We found that the HPS/FGL1 level was significantly upregulated in KRAS-mutated PDAC cells and was involved in KRAS/phosphorylated (p)-signal transduction and activator of transcription 3 (STAT3) signaling, and the knockdown of HPS/FGL1 in SUIT-2 cells decreased cell proliferation through increasing G2/M cell cycle arrest and cyclin B1 expression. In addition, the knockdown of HPS/FGL1 in SUIT-2 cells significantly increased omega-3 polyunsaturated fatty acids (PUFAs) and EPA production but not docosahexaenoic acid (DHA). Moreover, EPA treatment in SUIT-2 cells reduced the expression of de novo lipogenic protein, acetyl coenzyme A carboxylase (ACC)-1, and decreased p-STAT3 and HPS/FGL1 expressions, resulting in the suppression of cell viability. Conclusions: Results of this study indicate that HPS is highly expressed by KRAS-mutated PDAC cells, and HPS/FGL1 plays a crucial role in altering lipid metabolism and increasing cell growth in pancreatic cancer. EPA supplements could potentially inhibit or reduce ACC-1-involved lipogenesis and HPS/FGL1-mediated cell survival in KRAS-mutated pancreatic cancer cells. View Full-Text
Keywords: pancreatic cancer; KRAS mutation; hepassocin; eicosapentaenoic acid pancreatic cancer; KRAS mutation; hepassocin; eicosapentaenoic acid
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MDPI and ACS Style

Chiu, C.-F.; Hsu, M.-I.; Yeh, H.-Y.; Park, J.M.; Shen, Y.-S.; Tung, T.-H.; Huang, J.-J.; Wu, H.-T.; Huang, S.-Y. Eicosapentaenoic Acid Inhibits KRAS Mutant Pancreatic Cancer Cell Growth by Suppressing Hepassocin Expression and STAT3 Phosphorylation. Biomolecules 2021, 11, 370. https://doi.org/10.3390/biom11030370

AMA Style

Chiu C-F, Hsu M-I, Yeh H-Y, Park JM, Shen Y-S, Tung T-H, Huang J-J, Wu H-T, Huang S-Y. Eicosapentaenoic Acid Inhibits KRAS Mutant Pancreatic Cancer Cell Growth by Suppressing Hepassocin Expression and STAT3 Phosphorylation. Biomolecules. 2021; 11(3):370. https://doi.org/10.3390/biom11030370

Chicago/Turabian Style

Chiu, Ching-Feng; Hsu, Ming-I; Yeh, Hsiu-Yen; Park, Ji M.; Shen, Yu-Shiuan; Tung, Te-Hsuan; Huang, Jun-Jie; Wu, Hung-Tsung; Huang, Shih-Yi. 2021. "Eicosapentaenoic Acid Inhibits KRAS Mutant Pancreatic Cancer Cell Growth by Suppressing Hepassocin Expression and STAT3 Phosphorylation" Biomolecules 11, no. 3: 370. https://doi.org/10.3390/biom11030370

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