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Inhibitory role of TRIP-Br1 oncoprotein in anticancer drug-mediated programmed cell death via mitophagy activation

Samil Jung1, Davaajargal Myagmarjav1, Taeyeon Jo1

  • 1Division of Biological Sciences, Sookmyung Women's University, Seoul, 14310, South Korea.

International Journal of Biological Sciences
|July 11, 2022
PubMed

Insights

The oncoprotein TRIP-Br1 enhances breast cancer cell survival by activating mitophagy, a process that removes damaged mitochondria and suppresses programmed cell death (PCD) in response to chemotherapy.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Research

Background:

  • Chemotherapy is a cornerstone of cancer treatment, but its efficacy is often compromised by cancer cell resistance.
  • Cancer cells resist chemotherapy partly by evading programmed cell death (PCD).
  • Mitophagy, the selective degradation of damaged mitochondria, is implicated in conferring drug resistance to cancer cells.

Purpose of the Study:

  • To investigate the role of the oncoprotein TRIP-Br1 in chemoresistance.
  • To elucidate the mechanism by which cancer cells resist chemotherapy-induced PCD.
  • To determine the involvement of mitophagy in TRIP-Br1-mediated chemoresistance.

Main Methods:

  • Utilized breast cancer cell models treated with staurosporine (STS) to induce cell death.
  • Assessed TRIP-Br1 expression and localization in mitochondria following STS treatment.
  • Investigated the impact of TRIP-Br1 on reactive oxygen species (ROS) levels, mitophagy, and mitochondrial protein degradation.
  • Measured the expression of lysosomal proteases cathepsins B and D.

Main Results:

  • TRIP-Br1 levels increased in mitochondria of breast cancer cells post-chemotherapy.
  • STS treatment induced ROS, triggering TRIP-Br1 translocation to mitochondria via dephosphorylation by protein phosphatase 2A (PP2A).
  • Mitochondrial TRIP-Br1 suppressed ROS, enhanced mitophagy, and degraded key mitochondrial proteins (VDAC1, TOMM20, TIMM23), inhibiting STS-induced PCD.
  • TRIP-Br1 upregulated cathepsins B and D, crucial for lysosomal function in mitophagy.

Conclusions:

  • TRIP-Br1 promotes breast cancer cell survival by activating mitophagy and suppressing chemotherapy-induced PCD.
  • TRIP-Br1 functions as a key mediator of chemoresistance through mitochondrial quality control.
  • Targeting TRIP-Br1 or mitophagy pathways may represent a therapeutic strategy to overcome chemoresistance in breast cancer.
Keywords:
AutophagyCancerMitochondriaMitophagyTRIP-Br1

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