LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer

Abstract

BackgroundReprogrammed energy metabolism has become an emerging hallmark of cancer in recent years. Transporters have been reported to be amino acid sensors involved in controlling mTOR recruitment and activation, which is crucial for the growth of both normal and tumor cells. L-type amino acid transporter 2 (LAT2), encoded by the SLC7A8 gene, is a Na+-independent neutral amino acid transporter and is responsible for transporting neutral amino acids, including glutamine, which can activate mTOR. Previous studies have shown that LAT2 was overexpressed in gemcitabine-resistant pancreatic cancer cells. However, the role of LAT2 in chemoresistance in pancreatic cancer remains uncertain and elusive.MethodsThe effects of LAT2 on biological behaviors were analyzed. LAT2 and LDHB levels in tissues were detected, and the clinical value was evaluated.ResultsWe demonstrated that LAT2 emerged as an oncogenic protein and could decrease the gemcitabine sensitivity of pancreatic cancer cells in vitro and in vivo. The results of a survival analysis indicated that high expression levels of both LAT2 and LDHB predicted a poor prognosis in patients with pancreatic cancer. Furthermore, we found that LAT2 could promote proliferation, inhibit apoptosis, activate glycolysis and alter glutamine metabolism to activate mTOR in vitro and in vivo. Next, we found that gemcitabine combined with an mTOR inhibitor (RAD001) could reverse the decrease in chemosensitivity caused by LAT2 overexpression in pancreatic cancer cells. Mechanistically, we demonstrated that LAT2 could regulate two glutamine-dependent positive feedback loops (the LAT2/p-mTORSer2448 loop and the glutamine/p-mTORSer2448/glutamine synthetase loop) to promote glycolysis and decrease gemcitabine (GEM) sensitivity in pancreatic cancer.ConclusionTaken together, our data reveal that LAT2 functions as an oncogenic protein and could regulate glutamine-dependent mTOR activation to promote glycolysis and decrease GEM sensitivity in pancreatic cancer. The LAT2-mTOR-LDHB pathway might be a promising therapeutic target in pancreatic cancer.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0947-4) contains supplementary material, which is available to authorized users.

Metabolism of pancreatic cancer: paving the way to better anticancer strategies

“…In our previous research, we found that L-type amino acid transporter 2 (LAT2), an oncogenic protein in pancreatic cancer cells, could Gln-dependently activate mTOR to inhibit apoptosis and promote glycolysis. Both of them give rise to the gemcitabine-resistant phenotype, whereas mTOR inhibitor (RAD001) could solve such gemcitabine resistance [152]. Overexpressed Nampt provides massive NAD, sustaining enhanced glycolytic activity and contributing to gemcitabine resistance as well.…”

“…Enhanced Gln metabolism fuels elevated HBP and glycosylation. Moreover, Gln addiction is also significant for controlling ROS generation and activating mTOR, both of which contribute to chemoresistance [152,156]. ROS production in pancreatic cancer cells triggered by gemcitabine treatment is presumed to be related to the dose.…”

Take Advantage of Glutamine Anaplerosis, the Kernel of the Metabolic Rewiring in Malignant Gliomas

“…The transporters capable of importing glutamine such as ATB 0,+ ( SLC6A14 gene), SNAT1 ( SLC38A1 gene), ASCT2 ( SLC1A5 gene), LAT1 ( SLC7A5 gene), and LAT2 ( SLC7A8 gene) [ 42 ] are crucial in cancer metabolic remodeling often being upregulated in tumors [ 43 , 44 , 45 , 46 , 47 ]. Therefore, glutamine transport targeting is currently being addressed in pre-clinical trials.…”

Uncovering Prognosis-Related Genes and Pathways by Multi-Omics Analysis in Lung Cancer

“…Therefore, further studies in this area are required and could have the potential to contribute to the field of cancer research, and more particularly lung cancer. SLC7A8 or LAT-2 is an L-type amino acid transporter-2 protein that binds and regulates mechanistic target of rapamycin kinase (mTOR) activation in pancreatic cancer [69]. L-type amino acid transporters are known to be novel targets for cancer therapy [70,71].…”