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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor

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PAR1 participates in the ability of multidrug resistance and tumorigenesis by controlling Hippo-YAP pathway

Daisuke Fujimoto1, Yuki Ueda1, Yasuo Hirono1

  • 1First Department of Surgery, Faculty of Medicine, University of Fukui, Fukui, Japan.

Oncotarget
|October 3, 2015
PubMed

Insights

Protease-activated receptor 1 (PAR1) signaling activates gastric cancer stem cells by inhibiting the Hippo-YAP pathway. This promotes tumor growth and drug resistance, suggesting YAP as a therapeutic target.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Signaling

Background:

  • The Hippo pathway regulates organ size and is implicated in tumorigenesis.
  • Yeast Andematopoeisis/Transcriptional Activator (YAP)/Tazor (TAZ) are key Hippo pathway transducers essential for cancer stem cell (CSC) self-renewal and tumor initiation.
  • Upstream regulators of the mammalian Hippo pathway remain largely uncharacterized.

Purpose of the Study:

  • To investigate the link between Protease-activated receptor 1 (PAR1) signaling and the Hippo-YAP pathway in gastric cancer stem-like cells.
  • To elucidate the mechanisms by which PAR1 influences CSC characteristics and tumorigenesis.

Main Methods:

  • Utilized a selective PAR1 agonist (TFLLR-NH2) to activate PAR1 signaling in gastric cancer stem-like cells.
  • Assessed changes in side population cell fraction, tumorigenesis, drug resistance, cell morphology, invasion, and epithelial-mesenchymal transition (EMT).
  • Investigated the impact of PAR1 activation on the Hippo-YAP pathway, including Lats kinase activity and YAP nuclear localization, via Rho GTPase.

Main Results:

  • PAR1 activation increased the proportion of CSC-enriched side population cells, promoting tumorigenesis, multi-drug resistance, invasion, and morphological changes.
  • PAR1 activation inhibited Lats kinase activity through Rho GTPase, leading to increased nuclear YAP localization.
  • PAR1 signaling conferred CSC traits via the Hippo-YAP pathway and correlated with PAR1-induced EMT.

Conclusions:

  • PAR1 signaling plays a critical role in gastric cancer stem-like cell drug resistance and tumorigenesis through interaction with the Hippo-YAP pathway.
  • PAR1 activation promotes CSC characteristics and EMT in gastric cancer.
  • Inhibited YAP represents a potential therapeutic target for gastric cancer invasion and metastasis driven by dysregulated PAR1 signaling.
Keywords:
Hippo-YAP pathwayPAR1drug resistancegastric cancertumorigenesis

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