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

Ching-Feng Chiu1,2,3, Ming-I Hsu1,4, Hsiu-Yen Yeh5

  • 1Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei 11031, Taiwan.

Biomolecules
|April 3, 2021
PubMed
Abstract

Insights

Hepassocin (HPS/FGL1) is upregulated in KRAS-mutant pancreatic cancer, promoting cell growth and altering lipid metabolism. Eicosapentaenoic acid (EPA) may inhibit HPS/FGL1 and lipogenesis, offering a potential therapeutic strategy for KRAS-mutant pancreatic ductal adenocarcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are key drivers in pancreatic ductal adenocarcinoma (PDAC).
  • Hepassocin (HPS/FGL1) influences lipid metabolism and cancer progression, but its role in KRAS-mutant PDAC treated with eicosapentaenoic acid (EPA) is not fully understood.

Purpose of the Study:

  • To investigate the mechanism of HPS/FGL1 in KRAS-mutant PDAC cells.
  • To evaluate the effects of EPA on HPS/FGL1 expression and lipid metabolism in PDAC.
  • To explore the therapeutic potential of EPA in KRAS-mutant pancreatic cancer.

Main Methods:

  • Western blot analysis of HPS/FGL1 expression in PDAC cell lines with varying KRAS mutation status.
  • Gene knockdown of HPS/FGL1 and assessment of cell viability, proliferation, and cell cycle progression.
  • Lipidomic analysis to profile metabolic changes post-HPS/FGL1 knockdown.
  • Treatment of cells with EPA and evaluation of lipogenic and signaling pathway markers.

Main Results:

  • HPS/FGL1 was significantly upregulated in KRAS-mutant PDAC cells, correlating with KRAS/p-STAT3 signaling.
  • HPS/FGL1 knockdown reduced cell proliferation by inducing G2/M cell cycle arrest and affecting cyclin B1 expression.
  • HPS/FGL1 knockdown increased omega-3 polyunsaturated fatty acids (PUFAs), specifically EPA production.
  • EPA treatment suppressed cell viability by reducing de novo lipogenic protein ACC-1 and decreasing p-STAT3 and HPS/FGL1 expression.

Conclusions:

  • HPS/FGL1 is highly expressed in KRAS-mutant PDAC, driving cell growth and altering lipid metabolism.
  • EPA shows potential to inhibit lipogenesis via ACC-1 and reduce cell survival mediated by HPS/FGL1 in KRAS-mutant pancreatic cancer.
Keywords:
KRAS mutationeicosapentaenoic acidhepassocinpancreatic cancer

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