Major Finding: A variant of SLC1A5 (SLC1A5_var) fueled pancreatic cancer cells' mitochondria with glutamine.
Mechanism: Hypoxia upregulated SLC1A5_var via increased HIF2α binding at the SLC1A5_var promoter.
Impact: SLC1A5_var knockdown inhibited pancreatic tumor growth in mice, so it may be a target of interest.
Glutamine is known to play an especially important role in metabolism in cancer cells, yet the identity of the mitochondrial glutamine transporter has remained elusive. Yoo and colleagues found evidence that the transporter in question is a variant of SLC1A5 (dubbed SLC1A5_var), a sodium-dependent transporter of neutral amino acids. This variant, which is produced via transcription of the SLC1A5 gene at an alternative transcriptional start site, contains an N-terminal mitochondrial targeting signal. Whereas SLC1A5 localized to the plasma membrane in a human pancreatic cancer cell line, SLC1A5_var was found on mitochondrial membranes, and SLC1A5_var functioned as a mitochondrial glutamine transporter in the cells. Interestingly, the expression of SLC1A5_var was activated by hypoxia in an HIF2α-dependent fashion, and HIF2α binding was observed at the promoter region of SLC1A5_var under hypoxic conditions. SLC1A5_var was also essential for mitochondrial glutaminolysis, and ATP production via this process depended greatly on SLC1A5_var. Mechanistically, SLC1A5_var regulated the synthesis of the antioxidant glutathione from glutamine, implying that the variant may play an important part in regulation of reactive oxygen species (ROS) levels and the cellular redox state. Further experiments supported a role for the glutamine influx mediated by SLC1A5_var in mitochondrial respiration and glycolysis. In pancreatic cancer cell lines and patient-derived pancreatic cancer cells, resistance to the chemotherapeutic drug gemcitabine caused by hypoxia was determined to be mediated by SLC1A5_var via the reduction in ROS that resulted from glutamine-dependent glutathione synthesis. Notably, SLC1A5_var was essential for pancreatic cancer cell growth in vitro, and experiments in mouse xenograft models of pancreatic cancer showed that shRNA-mediated knockdown of SLC1A5_var inhibited tumor growth. Collectively, these experiments provide strong evidence that SLC1A5_var is a mitochondrial glutamine transporter important in cancer-cell metabolism and implicate it as a potential therapeutic target.
Notes
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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Volume 10, Issue 2
