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The tumor suppressor NDRG2 cooperates with an mTORC1 inhibitor to suppress the Warburg effect in renal cell carcinoma

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Summary

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.

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References

  1. Linehan WM, Srinivasan R, Schmidt LS (2010) The genetic basis of kidney cancer: a metabolic disease. Nat Rev Urol 7(5):277–285. https://doi.org/10.1038/nrurol.2010.47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kaelin WG Jr (2007) The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma. Clin Cancer Res 13(2 Pt 2):680s–684s. https://doi.org/10.1158/1078-0432.CCR-06-1865

    Article  CAS  PubMed  Google Scholar 

  3. Pal SK, Quinn DI (2013) Differentiating mTOR inhibitors in renal cell carcinoma. Cancer Treat Rev 39(7):709–719. https://doi.org/10.1016/j.ctrv.2012.12.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cardillo TM, Trisal P, Arrojo R, Goldenberg DM, Chang CH (2013) Targeting both IGF-1R and mTOR synergistically inhibits growth of renal cell carcinoma in vitro. BMC Cancer 13:170. https://doi.org/10.1186/1471-2407-13-170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Deng Y, Yao L, Chau L, Ng SS, Peng Y, Liu X, Au WS, Wang J, Li F, Ji S, Han H, Nie X, Li Q, Kung HF, Leung SY, Lin MC (2003) N-Myc downstream-regulated gene 2 (NDRG2) inhibits glioblastoma cell proliferation. Int J Cancer 106(3):342–347. https://doi.org/10.1002/ijc.11228

    Article  CAS  PubMed  Google Scholar 

  6. Hu XL, Liu XP, Deng YC, Lin SX, Wu L, Zhang J, Wang LF, Wang XB, Li X, Shen L, Zhang YQ, Yao LB (2006) Expression analysis of the NDRG2 gene in mouse embryonic and adult tissues. Cell Tissue Res 325(1):67–76. https://doi.org/10.1007/s00441-005-0137-5

    Article  CAS  PubMed  Google Scholar 

  7. Ma J, Jin H, Wang H, Yuan J, Bao T, Jiang X, Zhang W, Zhao H, Yao L (2008) Expression of NDRG2 in clear cell renal cell carcinoma. Biol Pharm Bull 31(7):1316–1320

    Article  CAS  Google Scholar 

  8. Liang ZL, Kang K, Yoon S, Huang SM, Lim JS, Kim JM, Lim JS, Lee HJ (2012) NDRG2 is involved in the oncogenic properties of renal cell carcinoma and its loss is a novel independent poor prognostic factor after nephrectomy. Ann Surg Oncol 19(8):2763–2772. https://doi.org/10.1245/s10434-011-2204-3

    Article  PubMed  Google Scholar 

  9. Wu Z, Liao H, Su J, Yang L, Chi Z, OuYang X (2014) Adenovirus-mediated NDRG2 inhibits the proliferation of human renal cell carcinoma cell line OS-RC-2 in vitro. Cell Biochem Biophys 70(1):593–600. https://doi.org/10.1007/s12013-014-9961-0

    Article  CAS  PubMed  Google Scholar 

  10. Ma JJ, Kong LM, Liao CG, Jiang X, Wang Y, Bao TY (2012) Suppression of MMP-9 activity by NDRG2 expression inhibits clear cell renal cell carcinoma invasion. Med Oncol 29(5):3306–3313. https://doi.org/10.1007/s12032-012-0265-1

    Article  CAS  PubMed  Google Scholar 

  11. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013

    Article  CAS  Google Scholar 

  12. Xu X, Li J, Sun X, Guo Y, Chu D, Wei L, Li X, Yang G, Liu X, Yao L, Zhang J, Shen L (2015) Tumor suppressor NDRG2 inhibits glycolysis and glutaminolysis in colorectal cancer cells by repressing c-Myc expression. Oncotarget 6(28):26161–26176. https://doi.org/10.18632/oncotarget.4544

    Article  PubMed  PubMed Central  Google Scholar 

  13. Pan T, Zhang M, Zhang F, Yan G, Ru Y, Wang Q, Zhang Y, Wei X, Xu X, Shen L, Zhang J, Wu K, Yao L, Li X (2017) NDRG2 overexpression suppresses hepatoma cells survival during metabolic stress through disturbing the activation of fatty acid oxidation. Biochem Biophys Res Commun 483(2):860–866. https://doi.org/10.1016/j.bbrc.2017.01.018

    Article  CAS  PubMed  Google Scholar 

  14. Roulin D, Waselle L, Dormond-Meuwly A, Dufour M, Demartines N, Dormond O (2011) Targeting renal cell carcinoma with NVP-BEZ235, a dual PI3K/mTOR inhibitor, in combination with sorafenib. Mol Cancer 10:90. https://doi.org/10.1186/1476-4598-10-90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ramakrishnan V, Timm M, Haug JL, Kimlinger TK, Wellik LE, Witzig TE, Rajkumar SV, Adjei AA, Kumar S (2010) Sorafenib, a dual Raf kinase/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs. Oncogene 29(8):1190–1202. https://doi.org/10.1038/onc.2009.403

    Article  CAS  PubMed  Google Scholar 

  16. Karoulia Z, Gavathiotis E, Poulikakos PI (2017) New perspectives for targeting RAF kinase in human cancer. Nat Rev Cancer 17(11):676–691. https://doi.org/10.1038/nrc.2017.79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. De Mulder PH (2007) Targeted therapy in metastatic renal cell carcinoma. Ann Oncol 18(Suppl 9):ix98–ix102. https://doi.org/10.1093/annonc/mdm303

    Article  PubMed  Google Scholar 

  18. Barthelemy P, Hoch B, Chevreau C, Joly F, Laguerre B, Lokiec F, Duclos B (2013) mTOR inhibitors in advanced renal cell carcinomas: from biology to clinical practice. Crit Rev Oncol Hematol 88(1):42–56. https://doi.org/10.1016/j.critrevonc.2013.02.006

    Article  PubMed  Google Scholar 

  19. Nakahata S, Ichikawa T, Maneesaay P, Saito Y, Nagai K, Tamura T, Manachai N, Yamakawa N, Hamasaki M, Kitabayashi I, Arai Y, Kanai Y, Taki T, Abe T, Kiyonari H, Shimoda K, Ohshima K, Horii A, Shima H, Taniwaki M, Yamaguchi R, Morishita K (2014) Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers. Nat Commun 5:3393. https://doi.org/10.1038/ncomms4393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hardie DG (2014) AMPK--sensing energy while talking to other signaling pathways. Cell Metab 20(6):939–952. https://doi.org/10.1016/j.cmet.2014.09.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Semenza GL (2010) HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20(1):51–56. https://doi.org/10.1016/j.gde.2009.10.009

    Article  CAS  PubMed  Google Scholar 

  22. Aoki M, Fujishita T (2017) Oncogenic roles of the PI3K/AKT/mTOR Axis. Curr Top Microbiol Immunol 407:153–189. https://doi.org/10.1007/82_2017_6

    Article  PubMed  Google Scholar 

Download references

Funding

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).

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Author notes

  1. Xi’an Li, Guangdong Hou and Zheng Zhu contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China

    Xi’an Li, Guangdong Hou, Zheng Zhu, Fuli Wang, Di Wei, Yu Zheng, Wanxiang Zheng, Geng Zhang, Ping Meng & Jianlin Yuan

  2. Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, Shaanxi, China

    Xi’an Li, Yan Guo, Xia Li, Libo Yao & Lan Shen

  3. Department of Gene Technology, Fourth Military Medical University, Xi’an, Shaanxi, China

    Fei Yan

  4. School of Medicine, St. George’s University, West Indies, Grenada

    Jiarui Yuan

Authors
  1. Xi’an Li
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  2. Guangdong Hou
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  15. Lan Shen
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Corresponding authors

Correspondence to Lan Shen or Jianlin Yuan.

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Ethical approval

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.

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Highlights

• The mTORC1 inhibitors can suppress aerobic glycolysis in RCC

• The mTORC1 inhibitor everolimus inhibits aerobic glycolysis-related enzymes in RCC via HIF1α

• The tumor suppressor NDRG2 reduces activation of the mTORC1 pathway and HIF1α expression

• The tumor suppressor NDRG2 cooperates with everolimus to inhibit aerobic glycolysis in RCC

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Li, X., Hou, G., Zhu, Z. et al. The tumor suppressor NDRG2 cooperates with an mTORC1 inhibitor to suppress the Warburg effect in renal cell carcinoma. Invest New Drugs 38, 956–966 (2020). https://doi.org/10.1007/s10637-019-00839-8

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  • DOI: https://doi.org/10.1007/s10637-019-00839-8

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