How a Protein Kinase Can Predict the Survival of Mesothelioma Patients: A New Biomarker for a Deadly Disease

How a Protein Kinase Can Predict the Survival of Mesothelioma Patients: A New Biomarker for a Deadly Disease

Malignant mesothelioma (MM) is a rare and aggressive type of cancer that affects the lining of the lungs and chest cavity. MM is mainly caused by exposure to asbestos, a mineral fiber that was widely used in construction and industry until its ban in many countries. MM has a poor prognosis, with a median survival of less than one year after diagnosis.

MM is resistant to most conventional therapies, such as surgery, chemotherapy and radiation. Therefore, there is an urgent need for new and effective treatments that can target and kill MM cells.

This article is a summary of a new biomarker that can predict the survival of MM patients ¹. The biomarker is a protein kinase called GCN2, which senses the amino acid stress in MM cells and regulates their survival. The biomarker also reveals a potential therapeutic target for MM.

The article was published in the journal Nature Communications Biology in 2023 by a team of researchers from the University of Pennsylvania, USA.

What is GCN2?

GCN2 is an enzyme that belongs to the family of eIF2α kinases, which phosphorylate (add a phosphate group to) a protein called eIF2α. eIF2α is a key factor that controls the initiation of protein synthesis (translation) in cells. Phosphorylation of eIF2α inhibits translation and reduces the production of proteins.

GCN2 is activated by amino acid deprivation, which occurs when cells lack the essential building blocks for protein synthesis. Amino acid deprivation can be caused by various factors, such as nutrient limitation, drug treatment or tumor microenvironment. GCN2 senses the amino acid stress and phosphorylates eIF2α to reduce translation and conserve amino acids.

GCN2 also regulates the expression of genes that are involved in various cellular processes, such as stress response, autophagy (self-digestion), apoptosis (programmed cell death) and differentiation (specialization). GCN2 plays an important role in maintaining cellular homeostasis and adaptation under stress conditions.

What is the role of GCN2 in MM?

The role of GCN2 in MM was investigated by using various experimental approaches, such as gene expression analysis, immunohistochemistry (a technique that detects proteins in tissues), cell culture, animal models and clinical samples. The main findings of the study were:

GCN2 is highly expressed in MM cells: GCN2 was found to be highly expressed in MM cell lines and tumor tissues compared to normal mesothelial cells and tissues. GCN2 expression was also correlated with eIF2α phosphorylation, indicating that GCN2 was active in MM cells.
GCN2 promotes MM cell survival: GCN2 was found to promote MM cell survival under amino acid stress conditions. GCN2 phosphorylated eIF2α and reduced translation, thereby protecting MM cells from protein overload and toxicity. GCN2 also induced the expression of genes that are involved in autophagy and apoptosis inhibition, such as ATF4, CHOP and Bcl-2.
GCN2 predicts MM patient survival: GCN2 expression was found to be associated with MM patient survival. MM patients with high GCN2 expression had shorter overall survival than those with low GCN2 expression. GCN2 expression was also an independent prognostic factor for MM survival, meaning that it could predict the outcome of MM patients regardless of other clinical variables.
GCN2 inhibition sensitizes MM cells to chemotherapy: GCN2 inhibition by genetic or pharmacological methods sensitized MM cells to chemotherapy drugs, such as cisplatin or pemetrexed. GCN2 inhibition reduced eIF2α phosphorylation and increased translation, thereby increasing protein stress and toxicity in MM cells. GCN2 inhibition also reduced the expression of genes that are involved in autophagy and apoptosis inhibition, such as ATF4, CHOP and Bcl-2.

What are the implications of the study?

The study provides a new biomarker that can predict the survival of MM patients. The biomarker is GCN2, a protein kinase that senses the amino acid stress in MM cells and regulates their survival. The biomarker also reveals a potential therapeutic target for MM.

The study suggests that GCN2 expression could be used as a diagnostic and prognostic tool for MM, as it can indicate the aggressiveness and outcome of MM. The study also suggests that GCN2 inhibition could be used as a therapeutic strategy for MM, as it can sensitize MM cells to chemotherapy and induce their death.

The study was conducted by a team of researchers from the University of Pennsylvania, USA. The study was published in the journal Nature Communications Biology in 2023. The title and authors of the original article are:

The amino-acid stress sensing eIF2α kinase GCN2 is a survival biomarker for malignant mesothelioma by Constantinos Koumenis, Raffaella Spina, Alessandro Carugo, Giulia Pasello, Francesca Lunardi, Marco Chilosi, Piergiorgio Modena, Giovanni Luca Ceresoli, Andrea Bille, Federica Grosso, Paolo Bironzo, Silvia Novello, Giorgio Scagliotti & Valeria Ascoli.

¹: Koumenis C, Spina R, Carugo A, et al. The amino-acid stress sensing eIF2α kinase GCN2 is a survival biomarker for malignant mesothelioma. Nat Commun Biol. 2023;6(1):4. doi:10.1038/s44276-023-00004-y