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Luteolin selectively kills STAT3 highly activated gastric cancer cells through enhancing the binding of STAT3 to

Shiyu Song1, Zhonglan Su2, Hui Xu1

  • 1Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China.

Cell Death & Disease
|February 10, 2017
PubMed

Insights

Luteolin, a plant flavonoid, selectively targets and kills drug-resistant gastric cancer cells by inhibiting STAT3 activation. This mechanism involves SHP-1 and HSP-90, leading to reduced tumor growth in vivo.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Gastric cancer (GC) remains a significant health challenge with limited treatment options for drug-resistant cases.
  • The precise mechanisms underlying the antitumor effects of plant-derived compounds like luteolin in GC are not fully elucidated.
  • Signal transducer and activator of transcription 3 (STAT3) is frequently overactivated in GC, contributing to tumor progression and drug resistance.

Purpose of the Study:

  • To investigate the antitumor effects of luteolin in gastric cancer cells.
  • To elucidate the molecular mechanisms by which luteolin exerts its effects, particularly in STAT3-overactivated and drug-resistant GC cells.
  • To evaluate the efficacy of luteolin in a preclinical gastric cancer model.

Main Methods:

  • In vitro studies using gastric cancer cell lines treated with luteolin.
  • Analysis of STAT3 phosphorylation, expression of STAT3 target genes (Mcl-1, Survivin, Bcl-xl), and apoptosis.
  • Silencing of SHP-1 (a protein tyrosine phosphatase) and investigation of its role in luteolin's effects.
  • Exploration of the involvement of HSP-90 in the luteolin-mediated STAT3 dephosphorylation pathway.
  • In vivo studies using a gastric cancer cell xenograft mouse model.

Main Results:

  • Luteolin selectively inhibited STAT3 phosphorylation and reduced the expression of STAT3-dependent genes (Mcl-1, Survivin, Bcl-xl) in GC cells.
  • Silencing of SHP-1 abrogated the inhibitory effects of luteolin on STAT3 and cell apoptosis, highlighting SHP-1's critical role.
  • Luteolin disrupted the HSP-90/STAT3 complex, facilitating STAT3 interaction with SHP-1 and subsequent dephosphorylation.
  • Luteolin treatment significantly inhibited tumor growth in a gastric cancer xenograft mouse model.

Conclusions:

  • Luteolin demonstrates potent antitumor activity against drug-resistant, STAT3-overactivated gastric cancer.
  • The mechanism involves SHP-1-mediated dephosphorylation of STAT3, potentially through disruption of the HSP-90/STAT3 complex.
  • Luteolin represents a promising therapeutic agent for gastric cancer, warranting further clinical investigation.

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