Effect of LAT2 on glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer.

Abstract

e15759 Background: Reprogrammed energy metabolism has become the characteristic of cancer recently. Transporters act as amino acid sensors involved in mTOR recruitment and activation, which is crucial for the growth of both normal and tumor cells. L-type amino acid transporter 2 (LAT2), a Na+ -independent neutral amino acid transporter, is encoded by the SLC7A8 gene and responsible for transporting neutral amino acids, including a mTOR activator, glutamine. LAT2 was reported to be overexpressed in gemcitabine-resistant pancreatic cancer cells. However, the role of LAT2 in chemoresistance in pancreatic cancer remains unclear. Methods: The effects of LAT2 on biological behaviors of pancreatic cancer cells were analyzed. LAT2 and LDHB levels in tissues were detected, and the clinical value was evaluated. Results: We demonstrated that LAT2 played an oncogenic role and decreased the gemcitabine sensitivity of pancreatic cancer cells in vitro and in vivo. Survival analysis indicated that high expression of both LAT2 and LDHB was related to 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, the combination of gemcitabine with an mTOR inhibitor (RAD001) could reverse the decrease in chemosensitivity caused by LAT2 overexpression in pancreatic cancer cells. Mechanistically, LAT2 promoted glycolysis and decreased gemcitabine sensitivity via regulating two glutamine-dependent positive feedback loops (the LAT2/p-mTORSer2448 loop and the glutamine/p-mTORSer2448/glutamine synthetase loop) in pancreatic cancer. Conclusions: Our data indicates that LAT2 functions as an oncogenic protein and could regulate glutamine-dependent mTOR activation to promote glycolysis and decrease gemcitabine sensitivity in pancreatic cancer. The LAT2-mTOR-LDHB pathway might be a promising therapeutic target in pancreatic cancer.