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Significance Statement
Non-small-cell lung carcinoma (NSCLC) accounts for 80% of lung cancer which is the first cause of malignancy related mortality worldwide, with more than one million cases diagnosed yearly. Mammalian target of rapamycin (mTOR) is an important regulator of cell growth and proliferation and involved in tumor development and progression. The dysregulation of mTOR was considered to be an appealing therapeutic target in a variety of cancers. mTOR is a well conserved serine/threonine kinase, which is the catalytic subunit of two molecular complexes of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Studies have suggested that mTORC1 plays a vital role in cell growth, autophagy, and cellular metabolism in various cancers. However, mTORC2 has not been thoroughly investigated in the metabolism of cancer cells. In this study, both mTORC1 and mTORC2 were found to be regulators of glycolytic metabolism in NSCLC cells, and the inhibition of either mTORC1 or mTORC2 decreased the cell glucose uptake. In addition, we found that NSCLC cells were significantly more sensitive to mTORC1/2 inhibitor than mTORC1 inhibitor. Moreover, treatment using AZD2014 combined with the cytostatic glycolysis inhibitor 2-DG synergistically and simultaneously induced the inhibition of cell proliferation and apoptosis in NSCLC cells. These results indicate that the combined application of mTORC1/2 and glycolysis inhibitors may be a better therapeutic approach for NSCLC than mTORC1/2 inhibitor alone. Our findings may lead to the application of a novel NSCLC therapeutics targeting both mTORC1/2 and glycolytic metabolism.
Figure legend: The combination index of mTOR inhibitors and glycolysis inhibitor on cell viability reduction in NSCLC cells.
(a) and (b) The dose–response curve of each drug was determined and the combination index (CI) values for rapamycin/2-DG concentration ratios (2:1) and AZD2014/2-DG concentration ratios(1:1) were calculated according to Chou–Talalay’s method at 48 h time point. CI < 1, CI = 1, and CI > 1 indicate synergistic, additive and antagonistic effects, respectively. The effect ranges from 0 (no inhibition) to 1 (complete inhibition). The data are representative of three.
Journal Reference
PLoS One. 2015 Jul 15;10(7):e0132880.
Jiang S1, Zou Z2, Nie P2, Wen R2, Xiao Y2, Tang J2.
[expand title=”Show Affiliations”]- Department of Oncology, the 2nd Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
- KingMed Diagnostics and KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China.
Abstract
Cancer metabolism has greatly interested researchers. Mammalian target of rapamycin (mTOR) is dysregulated in a variety of cancers and considered to be an appealing therapeutic target. It has been proven that growth factor signal, mediated by mTOR complex 1 (mTORC1), drives cancer metabolism by regulating key enzymes in metabolic pathways. However, the role of mTORC2 in cancer metabolism has not been thoroughly investigated. In this study, by employing automated spectrophotometry, we found the level of glucose uptake was decreased in non-small-cell lung carcinoma (NSCLC) A549, PC-9 and SK-MES-1 cells treated with rapamycin or siRNA against Raptor, indicating that the inhibition of mTORC1 attenuated glycolytic metabolism in NSCLC cells. Moreover, the inhibition of AKT reduced glucose uptake in the cells as well, suggesting the involvement of AKT pathway in mTORC1 mediated glycolytic metabolism. Furthermore, our results showed a significant decrease in glucose uptake in rictor down-regulated NSCLC cells, implying a critical role of mTORC2 in NSCLC cell glycolysis. In addition, the experiments for MTT, ATP, and clonogenic assays demonstrated a reduction in cell proliferation, cell viability, and colony forming ability in mTOR inhibiting NSCLC cells. Interestingly, the combined application of mTORC1/2 inhibitors and glycolysis inhibitor not only suppressed the cell proliferation and colony formation, but also induced cell apoptosis, and such an effect of the combined application was stronger than that caused by mTORC1/2 inhibitors alone. In conclusion, this study reports a novel effect of mTORC2 on NSCLC cell metabolism, and reveals the synergistic effects between mTOR complex 1/2 and glycolysis inhibitors, suggesting that the combined application of mTORC1/2 and glycolysis inhibitors may be a new promising approach to treat NSCLC.
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