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KATP Channel Expression Determines ONC212 Sensitivity via Mitochondrial Dysfunction and PERK/ATF4/CHOP Activation in

Ahmet Taskesen1, Ceyhan Hacioglu2

  • 1Department of Neurosurgery, Faculty of Medicine, Düzce University, Düzce, Turkey.

Journal of Cellular and Molecular Medicine
|July 26, 2026
PubMed

Insights

ATP-sensitive potassium (KATP) channel expression influences glioblastoma (GBM) sensitivity to ONC212. Inhibiting KATP channels enhances ONC212

Area of Science:

  • Neuro-oncology
  • Cancer Metabolism
  • Mitochondrial Biology

Background:

  • Glioblastoma (GBM) displays metabolic plasticity and therapy resistance, linked to mitochondrial function.
  • ONC212 targets mitochondrial proteostasis, but its efficacy determinants in GBM are unknown.
  • ATP-sensitive potassium (KATP) channels are implicated in cellular stress responses.

Purpose of the Study:

  • To investigate if KATP channel expression affects ONC212-induced mitochondrial dysfunction and integrated stress response (ISR) in GBM.
  • To determine the role of KATP channels in modulating GBM sensitivity to ONC212.

Main Methods:

  • Assessed ONC212 cytotoxicity in human GBM lines and astrocytes.
  • Quantified KATP subunit expression (Kir6.2, SUR1, CCDC51) via qRT-PCR and western blot.
  • Evaluated mitochondrial reactive oxygen species (ROS), oxygen consumption, PERK/ATF4/CHOP activation, and apoptosis.
  • Modulated KATP channels pharmacologically and using siRNA.

Main Results:

  • ONC212 exhibited tumor-selective cytotoxicity, with higher sensitivity in KATP-high GBM cells.
  • ONC212 induced mitochondrial ROS, impaired oxidative phosphorylation, and activated the PERK/ATF4/CHOP ISR pathway.
  • KATP inhibition potentiated ONC212 effects, increasing mitochondrial dysfunction, ISR activation, and apoptosis.
  • KCNJ11 (Kir6.2) silencing significantly enhanced ONC212 sensitivity.

Conclusions:

  • KATP channel expression modulates ONC212 responsiveness in GBM by influencing mitochondrial stress and ISR signaling.
  • Targeting KATP channels may enhance imipridone efficacy in GBM.
  • KATP channel modulation offers a potential strategy for metabolically guided GBM therapy.
Keywords:
KATP channelsONC212glioblastomaintegrated stress responsemipridonemitochondrial dysfunction

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