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.
Highlights
Reprogrammed energy metabolism has become an emerging hallmark of cancer in recent years
A high L-type amino acid transporter 2 (LAT2) level is associated with a poor prognosis The expression level of LAT2 in 87 pancreatic cancer tissue samples and 71 matched paracancerous tissues was evaluated by immunohistochemistry (IHC)
LAT2 targets glutamine-dependent mechanistic target of rapamycin (mTOR) activation to regulate apoptosis, glycolysis and chemosensitivity in pancreatic cancer cells we investigated whether the process by which LAT2 targets mTOR activation to regulate apoptosis, glycolysis and chemosensitivity in pancreatic cancer cells was dependent on glutamine
Summary
Reprogrammed 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. Previous studies have shown that LAT2 was overexpressed in gemcitabine-resistant pancreatic cancer cells. Previous studies indicated that most metabolites did not show significant changes in pancreatic cancer cells exposed to GEM; chemoresistance to GEM induces metabolic reprogramming [4, 5]. Glutamine and glucose are the primary nutrient sources for cancer cells and are crucial to the biosynthesis of products such as nucleic acids and nonessential amino acids (NEAAs) [6]. Other studies show that glutamine can activate mechanistic target of rapamycin (mTOR) [7] and inhibit apoptosis to induce chemoresistance [8]. Glutamine transport and metabolism might play an important role in chemoresistance in pancreatic cancer
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