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ONC201 Suppresses Neuroblastoma Growth by Interrupting Mitochondrial Function and Reactivating Nuclear ATRX

Jian-Ching Wu1, Chao-Cheng Huang2,3, Pei-Wen Wang1,4

  • 1Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.

International Journal of Molecular Sciences
|January 21, 2023
PubMed

Insights

ONC201 targets mitochondrial ClpXP proteases, offering a potential neuroblastoma (NB) therapy. This drug suppressed NB growth, promoted differentiation, and reduced MYCN expression in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Mitochondrial Biology

Background:

  • Neuroblastoma (NB) exhibits malignant phenotypes challenging to treat with monotherapy.
  • The role of mitochondrial ClpXP protease (ClpP and ClpX) in NB pathogenesis is unexplored.
  • ClpXP protease activity is implicated in various cancers, suggesting potential therapeutic relevance.

Purpose of the Study:

  • To investigate the expression and therapeutic potential of mitochondrial ClpXP proteases in neuroblastoma.
  • To evaluate the efficacy of ONC201, a ClpXP inhibitor, in preclinical NB models.
  • To elucidate the mechanisms underlying ONC201's effects on NB cell behavior and differentiation.

Main Methods:

  • Analysis of ClpP and ClpX expression in human neuroblastoma tissues.
  • Treatment of NB cells with ONC201 and short interfering RNA (siRNA) targeting ClpP/ClpX.
  • Assessment of mitochondrial function, including respiratory chain subunits (SDHB, NDUFS1), reactive oxygen species (ROS), and membrane potential.
  • Evaluation of apoptosis, cell growth, neurite outgrowth, and tumor suppressor ATRX expression.
  • In vivo studies using NB-cell-derived xenograft tumors in mice.

Main Results:

  • Increased ClpP and ClpX expression observed in human neuroblastoma tissues.
  • ONC201 treatment suppressed ClpXP expression, downregulated mitochondrial respiratory chain subunits, and induced energy depletion.
  • ONC201 and ClpP/ClpX knockdown promoted NB cell apoptosis, suppressed growth, upregulated ATRX, and induced neurite outgrowth.
  • ONC201 decreased MYCN protein levels and suppressed xenograft tumor formation, reactivating ATRX.
  • These findings implicate ClpXP in NB cell differentiation and highlight ONC201's potential.

Conclusions:

  • Mitochondrial ClpXP proteases are upregulated in neuroblastoma and represent a viable therapeutic target.
  • ONC201 effectively inhibits ClpXP, leading to energy depletion, apoptosis, and suppressed growth in NB cells.
  • ONC201 promotes NB differentiation, evidenced by ATRX upregulation and neurite outgrowth, particularly in MYCN-amplified NB.
  • ONC201 demonstrates significant potential as a therapeutic agent for neuroblastoma, especially in cases with MYCN amplification.
Keywords:
ATRXClpPX proteaseMYCNONC201apoptosismitochondrianeuroblastoma

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