The tumor suppressor NDRG2 cooperates with an mTORC1 inhibitor to suppress the Warburg effect in renal cell carcinoma
Renal cell carcinoma (RCC) is one of the most common malignancies worldwide, and metabolic reprogramming has a profound effect on RCC tumorigenesis. mTORC1 inhibitors are widely used in RCC treatment, yet some types of RCC cells are resistant to these compounds. Thus, clarification of the metabolic mechanism of mTORC1 inhibitors and exploration of new therapeutic approaches are urgently needed. In this study, we found that the mTORC1 pathway was hyperactive in RCC. Immunohistochemistry and western blot analysis showed that phosphorylation of the mTORC1 substrate 4EBP1 at threonine 37/46 increased in RCC tissues compared with that in normal renal tissues. It was also found that mTORC1 inhibitor everolimus suppressed glucose consumption, lactate production, and multiple catalytic enzymes involved in glycolysis in 786-O and ACHN cells, but the accumulation of HIF1α induced by CoCl2 blocked the inhibitory effect of everolimus on aerobic glycolysis. Interestingly, western blot and metabolite analysis showed that the tumor suppressor NDRG2 (N-Myc downstream regulated gene 2) was able to inhibit mTORC1 activity and cooperate with an mTOR inhibitor to decrease aerobic glycolysis in 786-O and ACHN cells. These results demonstrate that NDRG2 may potentially synergize with mTORC1 inhibitors to suppress malignant phenotype of RCC. Taken together, these data provided preclinical evidence that the combination of NDRG2 and mTORC1 inhibitors might be a promising strategy for RCC therapy.
KeywordsWarburg effect NDRG2 mTORC1 Everolimus Renal cell carcinoma
This study was funded by grants from the National Natural Science Foundation of China (Nos. 81672542, 81872420, 81402572, 31700667 and 81230043), the Natural Science Foundation of Shaanxi Province (2017SF-187, 2017SF-102, 2016SF-162, 2014JM4184), the Key Science and Technology Program of Shaanxi Province (2014 K11–03–05-01), and the Military Medical Innovation Projects (16CXZ023).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interests.
All experiments involved in this study were approved by both the Institutional Review Boards of The Fourth Military Medical University and the Ethics Committee of the above hospital.
Each patient provided a written consent prior to the study.
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