MYC‐driven inhibition of the glutamate‐cysteine ligase promotes glutathione depletion in liver cancer |
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| Authors: | Brittany Anderton Roman Camarda Sanjeev Balakrishnan Asha Balakrishnan Rebecca A Kohnz Lionel Lim Kimberley J Evason Olga Momcilovic Klaus Kruttwig Qiang Huang Guowang Xu Daniel K Nomura Andrei Goga |
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| Institution: | 1. Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA;2. Department of Medicine, University of California, San Francisco, San Francisco, CA, USA;3. Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, TWINCORE, Center for Experimental and Clinical Infection Research, Hannover, Germany;4. Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA;5. Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake, UT, USA;6. Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China |
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| Abstract: | How MYC reprograms metabolism in primary tumors remains poorly understood. Using integrated gene expression and metabolite profiling, we identify six pathways that are coordinately deregulated in primary MYC‐driven liver tumors: glutathione metabolism; glycine, serine, and threonine metabolism; aminoacyl‐tRNA biosynthesis; cysteine and methionine metabolism; ABC transporters; and mineral absorption. We then focus our attention on glutathione (GSH) and glutathione disulfide (GSSG), as they are markedly decreased in MYC‐driven tumors. We find that fewer glutamine‐derived carbons are incorporated into GSH in tumor tissue relative to non‐tumor tissue. Expression of GCLC, the rate‐limiting enzyme of GSH synthesis, is attenuated by the MYC‐induced microRNA miR‐18a. Inhibition of miR‐18a in vivo leads to increased GCLC protein expression and GSH abundance in tumor tissue. Finally, MYC‐driven liver tumors exhibit increased sensitivity to acute oxidative stress. In summary, MYC‐dependent attenuation of GCLC by miR‐18a contributes to GSH depletion in vivo, and low GSH corresponds with increased sensitivity to oxidative stress in tumors. Our results identify new metabolic pathways deregulated in primary MYC tumors and implicate a role for MYC in regulating a major antioxidant pathway downstream of glutamine. |
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| Keywords: | cancer glutathione metabolism miRNA
MYC
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