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TRAF4-mediated ubiquitination-dependent activation of JNK/Bcl-xL drives radioresistance

Xin Dong1, Xiaoying Li2, Yu Gan2

  • 1Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

Cell Death & Disease
|February 10, 2023
PubMed

Insights

Tumorigenesis factor TRAF4 (TNF receptor-associated factor 4) promotes colorectal cancer radioresistance. Blocking TRAF4 or Bcl-xL enhances radiotherapy effectiveness by promoting apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • TNF receptor-associated factor 4 (TRAF4) is an E3 ligase implicated in tumorigenesis and cancer progression.
  • The role of TRAF4 in colorectal cancer (CRC) radiosensitivity remains unclear.

Purpose of the Study:

  • To investigate the role of TRAF4 in colorectal cancer radiosensitivity.
  • To elucidate the underlying molecular mechanisms of TRAF4-mediated radioresistance.

Main Methods:

  • Analysis of TRAF4 expression in CRC clinical samples.
  • Assessment of TRAF4 depletion effects on CRC cell malignancy and radiosensitivity.
  • Investigation of the JNK/c-Jun signaling pathway activation by irradiation.
  • Evaluation of Bcl-xL transcription and its role in radioresistance.
  • In vitro and in vivo studies of TRAF4 or Bcl-xL inhibition combined with radiotherapy.

Main Results:

  • TRAF4 expression is significantly elevated in CRC tumors.
  • TRAF4 depletion reduces CRC cell malignancy and increases sensitivity to irradiation-induced cell death.
  • Irradiation activates JNK/c-Jun signaling through increased JNK ubiquitination and phosphorylation.
  • Activated c-Jun upregulates antiapoptotic Bcl-xL, contributing to radioresistance.
  • TRAF4 positively correlates with c-Jun and Bcl-xL.
  • Inhibition of TRAF4 or Bcl-xL enhances ionizing radiation-induced apoptosis and sensitizes CRC cells to radiotherapy.

Conclusions:

  • TRAF4 contributes to colorectal cancer radioresistance by activating the JNK/c-Jun/Bcl-xL pathway.
  • Targeting the TRAF4/Bcl-xL axis presents a potential therapeutic strategy to improve radiotherapy outcomes in CRC.

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