Abstract
The growth and development of non-small cell lung cancer (NSCLC) primarily depends on glutamine. Both glutamine and essential amino acids (EAAs) have been reported to upregulate mTOR in NSCLC, which is a bioenergetics sensor involved in the regulation of cell growth, cell survival, and protein synthesis. Seen as novel concepts in cancer development, ASCT2 and LAT transporters allow glutamine and EAAs to enter proliferating tumors as well as send a regulatory signal to mTOR. Blocking or downregulating these glutamine transporters in order to inhibit glutamine uptake would be an excellent therapeutic target for treatment of NSCLC. This study aimed to validate the metabolic dysregulation of glutamine and its derivatives in NSCLC using cellular 1H-NMR metabolomic approach while exploring the mechanism of delta-tocotrienol (δT) on glutamine transporters, and mTOR pathway. Cellular metabolomics analysis showed significant inhibition in the uptake of glutamine, its derivatives glutamate and glutathione, and some EAAs in both cell lines with δT treatment. Inhibition of glutamine transporters (ASCT2 and LAT1) and mTOR pathway proteins (P-mTOR and p-4EBP1) was evident in Western blot analysis in a dose-dependent manner. Our findings suggest that δT inhibits glutamine transporters, thus inhibiting glutamine uptake into proliferating cells, which results in the inhibition of cell proliferation and induction of apoptosis via downregulation of the mTOR pathway.
Highlights
Non-small cell lung cancer (NSCLC) presents itself as aggressive tumors arise from the airway epithelial cells and interior parts of the lungs [1]
The OPLS-DA score plot exhibited clear separation and treatment groups in A549 cells and H1299 cells with δT treatment; the high Q2 and R2 values between control and treatment groups in A549 cells and H1299 cells with δT treatment; the high Q2 indicate a considerable difference in the cellular metabolic profile of treated cells compared to control and R2 values indicate a considerable difference in the cellular metabolic profile of treated cells cells while validating the model that we used for OPLS-DA analysis
To identify the metabolites represented in the NMR spectral regions that varied between control and treatment groups, the corresponding loading S-Line plot from the OPLS-DA
Summary
Non-small cell lung cancer (NSCLC) presents itself as aggressive tumors arise from the airway epithelial cells (majority) and interior parts of the lungs [1]. Several studies report that there is a high probability of reoccurrence and development of resistance to drug therapies in NSCLC after treatment with chemotherapeutic agents, surgical resection, and radiation therapy [3]. This warrants efforts to identify novel therapeutic agents and targets for preventing and treating NSCLC
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