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MFF Regulation of Mitochondrial Cell Death Is a Therapeutic Target in Cancer

Jae Ho Seo1,2, Young Chan Chae3,2,4, Andrew V Kossenkov5

  • 1Prostate Cancer Discovery and Development Program.

Cancer Research
|October 5, 2019
PubMed

Insights

Scientists identified a new way to target cancer cell death by disrupting the MFF-VDAC1 complex. This novel approach shows promise for treating various cancers, including drug-resistant types, without harming normal cells.

Area of Science:

  • Cell Biology
  • Oncology
  • Biochemistry

Background:

  • Regulators of mitochondrial cell death in cancer are not well understood, limiting therapeutic development.
  • Mitochondrial dynamics, controlled by mitochondrial fission factor (MFF), are implicated in cancer progression.
  • Voltage-dependent anion channel-1 (VDAC1) is crucial for mitochondrial outer membrane permeability and cell death.

Purpose of the Study:

  • To investigate the role of MFF isoforms (MFF1 and MFF2) in non-small cell lung cancer.
  • To identify the interaction between MFF and VDAC1 as a potential therapeutic target.
  • To evaluate a novel peptidomimetic agent targeting the MFF-VDAC1 complex for anticancer activity.

Main Methods:

  • Assessed MFF1 and MFF2 overexpression in non-small cell lung cancer patients.
  • Characterized the complex formation between MFF and VDAC1 using structural analysis.
  • Developed and tested a cell-permeable peptidomimetic that disrupts the MFF-VDAC1 interaction.
  • Evaluated the compound's efficacy in various cancer cell lines, organoids, and patient-derived xenografts.

Main Results:

  • MFF1 and MFF2 were overexpressed in non-small cell lung cancer and formed complexes with VDAC1.
  • The MFF-VDAC1 interaction was structurally characterized, identifying key contact sites.
  • The MFF peptidomimetic disrupted the MFF-VDAC1 complex, induced mitochondrial depolarization, and triggered cancer cell death.
  • The peptidomimetic showed anticancer activity in diverse preclinical models, including drug-resistant cancers, with no observed toxicity in normal cells.

Conclusions:

  • The MFF-VDAC1 complex is a novel regulator of mitochondrial cell death and a viable therapeutic target in cancer.
  • A peptidomimetic targeting the MFF-VDAC1 complex demonstrates significant anticancer potential across multiple tumor types.
  • This study provides a new strategy for developing targeted cancer therapies by modulating mitochondrial cell death pathways.

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