Synergistic Effects between mTOR Complex 1/2 and Glycolysis Inhibitors in Non-Small-Cell Lung Carcinoma Cells
Suhua Jiang1, Zhengzhi Zou2, Peipei Nie2
1Department of Oncology, the 2nd Affiliated Hospital of 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.
Insights
This study reveals that inhibiting mTOR complex 1/2 (mTORC1/2) significantly reduces glucose uptake and proliferation in non-small-cell lung cancer (NSCLC) cells. Combining mTORC1/2 and glycolysis inhibitors offers a promising synergistic approach for NSCLC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Mammalian target of rapamycin (mTOR) is frequently dysregulated in cancers, making it a key therapeutic target.
- While mTOR complex 1 (mTORC1) is known to regulate cancer metabolism, the role of mTOR complex 2 (mTORC2) remains less understood.
- Non-small-cell lung carcinoma (NSCLC) exhibits altered metabolic pathways crucial for its growth.
Purpose of the Study:
- To investigate the role of mTOR complex 2 (mTORC2) in non-small-cell lung carcinoma (NSCLC) cell metabolism.
- To explore the impact of inhibiting mTORC1 and mTORC2 on NSCLC cell glycolysis, proliferation, and viability.
- To evaluate the synergistic effects of combined mTORC1/2 and glycolysis inhibition in NSCLC.
Main Methods:
- Automated spectrophotometry was used to measure glucose uptake in NSCLC cell lines (A549, PC-9, SK-MES-1).
- Rapamycin, siRNA against Raptor (mTORC1 inhibitor), and rictor (mTORC2 component) downregulation were employed.
- MTT, ATP, and clonogenic assays assessed cell proliferation, viability, and colony formation.
- Combined treatment with mTORC1/2 and glycolysis inhibitors was evaluated.
Main Results:
- Inhibition of mTORC1 significantly decreased glucose uptake and glycolytic metabolism in NSCLC cells.
- AKT pathway inhibition also reduced glucose uptake, indicating its involvement in mTORC1-mediated glycolysis.
- Downregulation of rictor demonstrated a critical role for mTORC2 in NSCLC glycolysis.
- Inhibition of mTORC1/2 reduced NSCLC cell proliferation, viability, and colony formation.
- Combined mTORC1/2 and glycolysis inhibition showed stronger suppression of proliferation and colony formation, and induced apoptosis compared to mTORC1/2 inhibition alone.
Conclusions:
- mTORC2 plays a critical role in regulating glycolysis in NSCLC cells.
- Combined inhibition of mTORC1/2 and glycolysis presents a synergistic and promising therapeutic strategy for NSCLC treatment.
- This study highlights a novel therapeutic avenue by targeting both mTOR signaling and cancer metabolism.
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