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DPYD, down-regulated by the potentially chemopreventive agent luteolin, interacts with STAT3 in pancreatic cancer

Hiroyuki Kato1, Aya Naiki-Ito1, Shugo Suzuki1

  • 1Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya,Japan.

Carcinogenesis
|February 28, 2021
PubMed

Insights

Luteolin (Lut) shows promise in preventing pancreatic cancer. This flavonoid suppressed tumor development and proliferation by targeting a novel STAT3-DPYD pathway, offering hope for pancreatic ductal carcinoma (PDAC) prevention.

Area of Science:

  • Oncology
  • Chemoprevention
  • Molecular Biology

Background:

  • Pancreatic ductal carcinoma (PDAC) has a poor prognosis, necessitating effective prevention strategies.
  • Flavonoids like Luteolin (Lut) and hesperetin (Hes) are potential chemopreventive agents, but their efficacy in PDAC is unstudied.
  • The BOP-induced hamster model is utilized to study pancreatic carcinogenesis.

Purpose of the Study:

  • To evaluate the chemopreventive effects of Luteolin (Lut) and hesperetin (Hes) on pancreatic carcinogenesis in vivo.
  • To investigate the molecular mechanisms underlying Lut's effects on pancreatic cancer cells.
  • To explore the correlation between DPYD expression, STAT3 activity, and PDAC prognosis in humans.

Main Methods:

  • Assessment of Lut and Hes in the BOP-induced hamster PDAC model.
  • In vitro studies on hamster and human pancreatic cancer cell proliferation.
  • Multi-blot, microarray, RNAi, and expression vector assays to analyze STAT3 and DPYD.
  • Immunohistochemical analysis of DPYD and Ki-67 in human PDAC tissues.

Main Results:

  • Lut, but not Hes, suppressed pancreatic intraepithelial neoplasia (PanIN) and reduced PDAC incidence and multiplicity.
  • Lut inhibited proliferation of both hamster and human pancreatic cancer cells in vitro.
  • Lut decreased phosphorylated STAT3 (pSTAT3) and dihydropyrimidine dehydrogenase (DPYD) expression.
  • DPYD expression and STAT3 activity were found to be interdependent and correlated with cell proliferation.
  • DPYD expression positively correlated with Ki-67 and indicated poor prognosis in human PDAC.

Conclusions:

  • Luteolin (Lut) is a potential chemopreventive agent for pancreatic ductal carcinoma (PDAC).
  • Lut acts by targeting a novel STAT3-DPYD pathway, inhibiting proliferation and tumor development.
  • DPYD expression is a potential biomarker for PDAC prognosis and is linked to STAT3 activity.

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