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RUNX3 enhances TRAIL-induced apoptosis by upregulating DR5 in colorectal cancer

Bo Ram Kim1, Seong Hye Park2, Yoon A Jeong2

  • 1Department of Oncology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea.

Oncogene
|January 30, 2019
PubMed

Insights

RUNX3 reactivation enhances cancer cell apoptosis through increased DR5 expression, particularly in response to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This RUNX3-TRAIL combination therapy shows anti-tumor effects in vivo.

Area of Science:

  • Cancer Biology
  • Molecular Oncology
  • Apoptosis Signaling

Background:

  • RUNX3 is frequently inactivated in various cancers due to DNA hypermethylation.
  • RUNX3 plays a role in regulating cell death pathways.
  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a key inducer of apoptosis.

Purpose of the Study:

  • To investigate the role of RUNX3 in TRAIL-induced apoptosis.
  • To explore the mechanisms by which RUNX3 modulates apoptosis.
  • To evaluate the therapeutic potential of combining RUNX3 and TRAIL.

Main Methods:

  • Overexpression of RUNX3 in cancer cells.
  • Analysis of death receptor (DR4 and DR5) expression.
  • Measurement of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress.
  • Inhibition of SOD3 transcription by RUNX3.
  • Assessment of apoptosis induction.
  • Evaluation of tumor growth in xenograft models.

Main Results:

  • RUNX3 overexpression increased DR5 expression, enhancing TRAIL-induced apoptosis.
  • RUNX3-induced DR5 upregulation involved ROS generation and CHOP activation.
  • RUNX3 inhibited SOD3 transcription, leading to increased ROS production.
  • Combined RUNX3 and TRAIL therapy reduced tumor growth in vivo.
  • No combined effect was observed in non-cancerous cells.

Conclusions:

  • RUNX3 directly promotes TRAIL-induced apoptosis by upregulating DR5.
  • RUNX3's mechanism involves ROS generation and ER stress.
  • RUNX3 acts as an anti-tumor agent, particularly when combined with TRAIL.

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