Recent research suggests that MYC activation in tumor cells leads to a unique metabolic phenotype that is characterized by glutamine addiction and TCA cycle activation. We wish to identify novel metabolic pathways that are altered in MYC-driven cancer in vivo. To that end, we have performed microarray-based transcriptomics and mass-spectrometry-based metabolomics profiling of tumors from a murine model of MYC-driven liver cancer. Using Fisher's exact test, we have identified glutathione metabolism as the most significantly enriched pathway across the two datasets. Notably, both the reduced and oxidized isoforms of glutathione, a major cellular antioxidant, are depleted in tumors relative to naïve control livers. We find that the rate-limiting enzyme of glutathione synthesis, Gclc, is attenuated by a MYC-regulated microRNA miR-18a. Loss of glutathione production is concomitant with increased glutamine conversion into TCA cycle metabolites in vivo. Despite loss of glutathione and another antioxidant, NADPH, our MYC-driven tumors do not exhibit markers of elevated oxidative stress. Instead, they appear to upregulate a host of alternative antioxidant pathways including Vitamin C and thioredoxins. In summary, while it is well established that MYC-driven tumors have increased dependence on glutamine resulting in increased glutamate production, whether MYC also regulates glutamate utilization decisions remains poorly understood. Here we show that MYC can regulate glutamate flux by attenuating glutathione production, shifting glutamate utilization towards the TCA cycle.
Citation Format: Brittany Anderton, Asha Balakrishnan, Sanjeev Balakrishnan, Lionel Lim, Rebecca Kohnz, Dan Nomura, Andrei Goga. MYC regulates glutathione depletion and glutamine utilization via miR-18a in vivo. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A01.
- ©2015 American Association for Cancer Research.