Anticancer activity delivered by targeting mitochondrial cell regulator
Disruption of the MFF-VDAC1 complex could lead to a potential therapeutic target for cancer.
A novel anticancer molecule has been created which showed therapeutic activity in pre-clinical models of various cancer types. This cell-permeable peptidomimetic was designed to disrupt a newly identified protein complex involving mitochondrial fission factor (MFF) and the voltage-dependent anion channel-1 (VDAC1), which regulates mitochondrial cell death.
The study by researchers at The Wistar Institute showed that MFF is highly expressed in cancer and interacts with VDAC1, a key regulator of mitochondrial cell death, to keep tumour cells alive.
“Disruption of the MFF-VDAC1 complex in vitro resulted in killing of cancer cells, pointing us in the direction of a potential therapeutic target,” said Dario C Altieri, MD, who is the senior author on the study. “The next step was to create a molecule that could disrupt the protein-protein interaction between MFF and VDAC1 and deliver pre-clinical anticancer activity without harming normal cells.”
The researchers analysed the structure of the MFF-VDAC1 interface to determine what portions of the MFF protein are required for its interaction with VDAC1. A synthetic peptide designed to contain these MFF regions was able to compete with MFF for binding to VDAC1, disrupting the interaction. As a result, this induced acute mitochondrial dysfunction and cell death.
This cell-permeable peptidomimetic was designed to disrupt a newly identified protein complex”
Treatment with the MFF peptide killed prostate cancer and melanoma cells, including drug-resistant cells. It did not affect the survival of normal prostate cells and fibroblasts, suggesting that transformed cells are more dependent on the integrity of the MFF-VDAC1 complex than normal cells.
Based on these studies, researchers then generated a cell-permeable peptidomimetic molecule, or a compound that mimics the inhibitory peptide, to target the complex in vivo for targeted cancer therapy.
This compound was tested in different pre-clinical settings. In all conditions, the peptidomimetic molecule effectively delivered potent anticancer activity.
“We are hopeful that this compound will be translated into a novel anticancer therapy with potential to be effective in multiple cancer types and less prone to drug resistance,” Altieri continued.
The study was published in Cancer Research.