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mTOR-targeted therapy: differential perturbation to mitochondrial membrane potential and permeability transition pore

Jae Eun Kim1, Qun He2, Yaqing Chen2

  • 1Oncology Research, Pfizer Pharmaceuticals, Pearl River, NY 10965, USA.

Biochemical and Biophysical Research Communications
|April 8, 2014
PubMed

Insights

mTOR inhibition impacts cancer cell mitochondria differently based on cell type. Sensitive cells show increased mitochondrial potential, while resistant cells exhibit reduced pore opening, affecting survival signaling and therapeutic outcomes.

Area of Science:

  • Mitochondrial dynamics in cancer biology
  • Molecular mechanisms of mTOR signaling
  • Cancer cell metabolism and bioenergetics

Background:

  • Mitochondria play a crucial role in cancer cell response to chemotherapy.
  • The mitochondrial response to mechanistic target of rapamycin (mTOR)-targeted anticancer therapy is not well understood.
  • mTOR signaling is frequently dysregulated in various cancers, making it a key therapeutic target.

Purpose of the Study:

  • To investigate the effects of mTOR inhibition on mitochondrial dynamics in diverse cancer cells.
  • To elucidate the differential mitochondrial responses in cancer cells with varying susceptibility to mTOR targeting.
  • To identify molecular mechanisms underlying mTOR-inhibitor-induced mitochondrial changes and their impact on cell survival.

Main Methods:

  • Utilized an allosteric rapalog, a selective mTOR kinase inhibitor (mTOR-KI), and mTOR-shRNA to target mTOR signaling.
  • Assessed mitochondrial membrane potential (mΔψ) and mitochondrial permeability transition pore (mPTP) opening in cancer cells.
  • Investigated the role of AKT-hexokinase 2 (HK2) binding to voltage-dependent anion channel (VDAC) in resistant cells.
  • Employed HK2-displacing peptide and methyl jasmonate to disrupt HK2-VDAC interaction.

Main Results:

  • Global mTOR targeting increased mΔψ in sensitive cancer cells (e.g., LNCap, MDA361, MG63) but not in resistant cells.
  • mTOR-KI treatment markedly reduced mPTP opening in resistant cancer cells (e.g., MDA231, HT29, HCT116), correlating with sustained AKT-HK2 survival signaling.
  • Resistant cells showed enhanced HK2 binding to VDAC, promoting mPTP closure and cell survival upon mTOR inhibition.
  • Disrupting HK2-VDAC interaction with specific agents blocked mPTP closure and enhanced growth suppression in resistant cells.

Conclusions:

  • mTOR inhibition induces complex and differential perturbations in mitochondrial dynamics across various cancer cell types.
  • The observed mitochondrial responses, particularly mPTP modulation via HK2-VDAC interaction in resistant cells, significantly influence therapeutic outcomes.
  • Understanding these differential mitochondrial effects is crucial for optimizing mTOR-targeted anticancer therapies.
Keywords:
AnticancerMitochondriamTOR inhibitor

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