CHTM1 regulates cancer cell sensitivity to metabolic stress via p38-AIF1 pathway

Recently, we have reported the characterization of a novel protein named Coiled-coil Helix Tumor and Metabolism 1 (CHTM1). CHTM1 localizes to both cytosol and mitochondria. Sequence corresponding to CHTM1 is also annotated in the database as CHCHD5. CHTM1 is deregulated in human breast and colon cancers and its deficiency in human cancer cells leads to defective lipid metabolism and poor growth under glucose/glutamine starvation.

Human cancer cell lines and tissue specimens were used. CHTM1 knockdown was done via lentiviral approach. CHTM1-expresssion constructs were developed and mutants were generated via site-directed mutagenesis approach. Western blotting, immunostaining, immunohistochemistry, cell fractionation and luciferase assays were performed. Reactive oxygen species and reactive nitrogen species were also measured.

Here we report that CHTM1 deficiency sensitizes human lung cancer cells to metabolic stress-induced cell death mediated by glucose/glutamine deprivation and metformin treatment. CHTM1 interacts with Apoptosis Inducing Factor 1 (AIF1) that is one of the important death inducing molecules. CHTM1 appears to negatively regulate AIF1 by preventing AIF1 translocation to cytosol/nucleus and thereby inhibit AIF1-mediated caspase-independent cell death. Our results also indicate that p38, a stress kinase, plays a critical role in metabolic stress-induced cell death in CHTM1-deficient cells. Furthermore, p38 appears to enhance AIF1 translocation from mitochondria to cytosol particularly in metabolically stressed CHTM1-deficient cells and CHTM1 negatively regulates p38 kinase activity. The expression status of CHTM1 in lung cancer patient samples is also investigated and our results indicate that CHTM1 levels are increased in the majority of lung tumors when compared to their matching normal tissues.

Thus, CHTM1 appears to be an important metabolic marker that regulates cancer cell survival under metabolic stress conditions, and has the potential to be developed as a predictive tumor marker.