ROS-Sensing Pathway Influences Mitochondrial Activity, Regulates Response to Cisplatin
Key findings
- Researchers at Mass General Brigham Cancer Institute have demonstrated a role for mitochondrial translation as a signaling hub that controls mitochondrial generation of reactive oxygen species (ROS)
- They identified a signaling pathway in which cytosolic ROS sensing by the protein VPS35 leads to an alteration in plasma membrane protein content, including the amino acid transporter SLC7A1, that affects mitochondrial translation
- Lower VPS35 levels correlated with earlier onset of platinum resistance in ovarian tumors, and VPS35 oxidation mutants conferred resistance to cisplatin in ovarian cancer cell models
- The oxidation status and/or protein levels of VPS35, as well as mitochondrial translation rates, may help to identify tumors that are sensitive to some subtypes of chemotherapeutic agents
Metabolic reprogramming is fundamental to cancer biology, as it allows tumor cells to sustain their malignant behaviors. One pivotal regulatory factor is oxidative stress, which induces genomic instability, oncogenic signaling activation, and tumor microenvironment remodeling, partly due to abnormal accumulation of reactive oxygen species (ROS).
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The control of ROS levels is thought to depend on proteins that sense ROS levels and regulate their production through their cysteine residues. Liron Bar-Peled, PhD, of the Krantz Family Center for Cancer Research at Mass General Brigham Cancer Institute, and colleagues, have discovered that mutations in a protein called VPS35 can prevent chemotherapy-induced cell death. They report their results in Nature.
Background: Potential Role of Mitochondrial Translation
In eukaryotic cells, ROS are mainly produced in mitochondria, and the electron transport chain (ETC) is central to this process. The ETC is composed of both nuclear and mitochondrially encoded proteins, and inhibition of any one ETC subunit results in increased cellular ROS. However, inhibition of the entire complex through blockade of mitochondrial translation leads to decreased ROS levels. Dr. Bar-Peled’s group wondered whether mitochondrial translation acts as a “central switch” within cells to control ROS levels.
Systematic Testing of Cysteines
The researchers used CRISPR base-editing screens to test more than 25,000 proteinaceous cysteines that could be important in regulating mitochondrial translation. They identified a signaling pathway in which cytosolic ROS sensing by VPS35 led to an alteration in plasma membrane protein content, including the amino acid transporter SLC7A1, that affected mitochondrial translation.
When mutated, two cysteine residues embedded in VPS35 (Cys653/Cys673) mediated resistance to four anti-cancer drugs that are partially dependent on mitochondrial translation for their cytotoxicity.
VPS35 and Resistance to Chemotherapy
The researchers then analyzed VPS35 expression in tumors from 24 patients with high-grade serous ovarian cancer. Patients who had lower levels of VPS35 in their tumors had earlier onset of platinum resistance.
Cisplatin functions in part by increasing steady-state ROS levels to mediate cell death. By depleting VSP35 in a panel of ovarian cancer cell models, the researchers directly demonstrated that loss of VPS35 mediates resistance to cisplatin. In some models, loss of VPS35 resulted in a more than 15-fold increase in cisplatin concentration compared with cells that were replete with VPS35.
Implications for Immunotherapy
These results suggest tumors might take advantage of increased ROS levels to decrease retromer function and reshape the immune response. As immunotherapies become front-line cancer treatment, resistance to them will be an even more important challenge.
Future research should address whether tumors take advantage of altered redox states to camouflage themselves from the immune system and, if so, how that knowledge can be applied to improving immune-based therapies.
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