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Romo1 Inhibition Induces TRAIL-Mediated Apoptosis in Colorectal Cancer

Min Jee Jo1, Bu Gyeom Kim1, Seong Hye Park1

  • 1Department of Oncology, Korea University Guro Hospital, Seoul 08308, Korea.

Cancers
|August 23, 2020
PubMed

Insights

Targeting reactive oxygen species modulator-1 (Romo1) enhances anti-cancer drug TRAIL efficacy in colorectal cancer. Romo1 inhibition sensitizes cancer cells to TRAIL-induced apoptosis via mitochondrial pathways, offering a novel therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows anti-cancer potential but faces limitations like short half-life and resistance.
  • Understanding molecular mechanisms of TRAIL sensitization is crucial for improving cancer therapy.
  • Reactive oxygen species modulator-1 (Romo1), upregulated in cancers, is a potential target for enhancing TRAIL efficacy.

Purpose of the Study:

  • To investigate Romo1 as a sensitizer for TRAIL-induced apoptosis in colorectal cancer.
  • To elucidate the molecular mechanisms underlying Romo1 inhibition-mediated sensitization to TRAIL.
  • To evaluate the therapeutic potential of combining TRAIL with Romo1 inhibition in preclinical models.

Main Methods:

  • Utilized colorectal cancer cell lines and a tumor xenograft model.
  • Investigated the effects of Romo1 inhibition alone and in combination with TRAIL on apoptosis induction.
  • Analyzed mitochondrial apoptosis pathways, including Bax/Parkin interaction and ubiquitin proteasome system (UPS).
  • Assessed reactive oxygen species (ROS) generation and mitochondrial function.

Main Results:

  • Romo1 inhibition significantly enhanced TRAIL-induced apoptosis in colorectal cancer cells, sparing normal cells.
  • The combination therapy activated mitochondrial apoptosis pathways, involving increased Bax levels via UPS downregulation.
  • Romo1 knockdown disrupted the Bax/Parkin interaction, leading to mitochondrial dysfunction and increased ROS.
  • Therapeutic efficacy was confirmed in an in vivo tumor xenograft model.

Conclusions:

  • Romo1 inhibition acts as an effective sensitizer for TRAIL-mediated apoptosis in colorectal cancer.
  • A novel mechanism involving the Bax/Parkin interaction and mitochondrial pathways underlies this sensitization.
  • Targeting Romo1 represents a promising therapeutic strategy for colorectal cancer treatment and drug discovery.
Keywords:
BaxParkinmitochondrial dysfunctionreactive oxygen species modulator-1tumor necrosis factor-related apoptosis-inducing ligand

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