Abstract 1115: p32 is a downstream effector of c-Myc induced glutamine addiction

Abstract

Abstract Genetic alterations of oncogenes and tumor suppressor genes are the main drivers not only of deregulated cell proliferation but also altered cancer cell metabolism. Compared with normal cells, malignant cells exhibit enhanced utilization of glucose and glutamine. As such, efforts to understand the molecular basis of the addiction to these two nutrients is likely to lead to the identification of new drug targets for the specific killing of cancer cells. A major player in tumor cell addiction to glutamine is the c-Myc oncogene. By stimulating the expression of glutamine transporters and glutaminase, this transcription factor promotes glutamine oxidation through the mitochondria. This rewiring of glutamine metabolism must be sustained by efficient mitochondrial function. The mitochondrial p32 protein was previously demonstrated to be critical in mitochondria metabolism by maintaining oxidative phosphorylation, yet the factors regulating its expression are not clear. Deregulated c-Myc is a frequent feature of gliomas and recent discoveries suggest the importance of metabolic alterations, in particular glutamine addiction, in the pathogenesis of these cancers. Interestingly, medulloblastoma can be clustered into six subgroups based on gene signature and the c-Myc amplified subgroup exhibits high p32 expression. In the present study, we hypothesized that p32 may be a downstream effector of c-Myc induced glutamine addiction. Using a c-Myc and estrogen receptor fusion protein construct in immortalized fibroblast, we demonstrated that p32 expression was up regulated upon c-Myc nuclear translocation. shRNA mediated stable knock-down of p32 in glioma cell lines and patient-derived tumor initiating cells impaired cell proliferation and tumorigenic potential in mouse models. Furthermore, attenuation of p32 expression reduced glioma cells sensitivity to glutamine deprivation and abrogated c-Myc induced glutamine consumption. Additional work is underway to determine whether c-Myc and p32 work in the same or parallel pathways to confer glutamine addiction on glioma cells and to establish the implications of this co-operation on tumor metabolism in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1115. doi:1538-7445.AM2012-1115