Article | Published:

Mitochondrial pyruvate carrier 1 functions as a tumor suppressor and predicts the prognosis of human renal cell carcinoma

Abstract

Invasion and subsequent metastasis are major characteristics of malignant human renal cell carcinoma (RCC), though the mechanisms remain elusive. Mitochondrial pyruvate carrier (MPC), a key factor that controls pyruvate transportation in mitochondria, is frequently dysregulated in tumor cells and loss of MPC predicts poor prognosis in various types of cancer. However, the clinical relevance and functional significance of MPC in RCC remain to be elucidated. In this study, we investigated the expression of MPC1 and MPC2 in specimens from RCC patients and observed downregulation of MPC1, but not MPC2, in RCC tissues compared with adjacent non-cancerous tissue. Moreover, RCC patients with higher MPC1 expression exhibited longer overall survival rate than those with lower MPC1. Functionally, MPC1 suppressed the invasion of RCC cells in vitro and reduced the growth of RCC cells in vivo, possibly through inhibition of MMP7 and MMP9. Further studies revealed that loss of MPC1 was induced by hypoxia in RCC cells, and notably, MPC1 expression, was negatively correlated with HIF1α expression in RCC cells and patient samples. Taken together, our results identify anti-tumor function of MPC1 in RCC and revealed MPC1 as a novel prognostic biomarker to predict better patient survival.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Levi F, Ferlay J, Galeone C, et al. The changing pattern of kidney cancer incidence and mortality in Europe. BJU Int. 2008;101:949–58.

  2. 2.

    Tan AS, Baty JW, Dong LF, et al. Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab. 2015;21:81–94.

  3. 3.

    Camarda R, Zhou AY, Kohnz RA. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat Med. 2016;22:427–32.

  4. 4.

    Herzig S, Raemy E, Montessuit S, et al. Identification and functional expression of the mitochondrial pyruvate carrier. Science. 2012;337:93–96.

  5. 5.

    Schell JC, Olson KA, Jiang L, et al. A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol Cell. 2014;56:400–13.

  6. 6.

    Wang L, Xu M, Qin J, et al. MPC1, a key gene in cancer metabolism, is regulated by COUPTFII in human prostate cancer. Oncotarget. 2016;7:14673–83.

  7. 7.

    Li X, Ji Y, Han G, et al. MPC1 and MPC2 expressions are associated with favorable clinical outcomes in prostate cancer. BMC Cancer. 2016;16:894.

  8. 8.

    Li Y, Li X, Kan Q, et al. Mitochondrial pyruvate carrier function is negatively linked to Warburg phenotype in vitro and malignant features in esophageal squamous cell carcinomas. Oncotarget. 2017;8:1058–73.

  9. 9.

    Ohashi T, Eguchi H, Kawamoto K, et al. Mitochondrial pyruvate carrier modulates the epithelial-mesenchymal transition in cholangiocarcinoma. Oncol Rep. 2018;39:1276–82.

  10. 10.

    Wu HB, Yang S, Weng HY, et al. Autophagy-induced KDR/VEGFR-2 activation promotes the formation of vasculogenic mimicry by glioma stem cells. Autophagy. 2017;13:1528–42.

  11. 11.

    Flores A, Schell J, Krall AS, et al. Lactate dehydrogenase activity drives hair follicle stem cell activation. Nat Cell Biol. 2017;19:1017–26.

  12. 12.

    Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res. 2004;10:7252–9.

  13. 13.

    Schell JC, Wisidagama DR, Bensard C, et al. Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. Nat Cell Biol. 2017;19:1027–36.

  14. 14.

    Mikami S, Oya M, Mizuno R, et al. Recent advances in renal cell carcinoma from a pathological point of view. Pathol Int. 2016;66:481–90.

  15. 15.

    Mehdi A, Riazalhosseini Y. Epigenome aberrations: emerging driving factors of the clear cell renal cell carcinoma. Int J Mol Sci. 2017;18:E1774.

  16. 16.

    Ma X, Gu L, Li H, et al. Hypoxia-induced overexpression of stanniocalcin-1 is associated with the metastasis of early stage clear cell renal cell carcinoma. J Transl Med. 2015;13:56.

  17. 17.

    Koh MY, Nguyen V, Lemos R Jr, et al. Hypoxia-induced SUMOylation of E3 ligase HAF determines specific activation of HIF2 in clear-cell renal cell carcinoma. Cancer Res. 2015;75:316–29.

  18. 18.

    Li P, Zhang D, Shen L, et al. Redox homeostasis protects mitochondria through accelerating ROS conversion to enhance hypoxia resistance in cancer cells. Sci Rep. 2016;6:22831.

  19. 19.

    Bell EL, Klimova T, Chandel NS. Targeting the mitochondria for cancer therapy: regulation of hypoxia-inducible factor by mitochondria. Antioxid Redox Signal. 2008;10:635–40.

  20. 20.

    Shweta, Mishra KP, Chanda S, et al. A comparative immunological analysis of CoCl2 treated cells with in vitro hypoxic exposure. Biometals. 2015;28:175–85.

  21. 21.

    Guan SY, Leng RX, Tao JH, et al. Hypoxia-inducible factor-1alpha: a promising therapeutic target for autoimmune diseases. Expert Opin Ther Targets. 2017;21:715–23.

  22. 22.

    Gudas LJ, Fu L, Minton DR, et al. The role of HIF1alpha in renal cell carcinoma tumorigenesis. J Mol Med. 2014;92:825–36.

  23. 23.

    Warburg O. On the origin of cancer cells. Science. 1956;123:309–14.

  24. 24.

    Eboli ML, Paradies G, Galeotti T, et al. Pyruvate transport in tumour-cell mitochondria. Biochim Biophys Acta. 1977;460:183–7.

  25. 25.

    Hiller K, Metallo CM. Profiling metabolic networks to study cancer metabolism. Curr Opin Biotechnol. 2013;24:60–68.

  26. 26.

    Yang C, Ko B, Hensley CT, et al. Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol Cell. 2014;56:414–24.

  27. 27.

    Compan V, Pierredon S, Vanderperre B, et al. Monitoring mitochondrial pyruvate carrier activity in real time using a BRET-based biosensor: investigation of the Warburg effect. Mol Cell. 2015;59:491–501.

  28. 28.

    Li X, Han G, Li X, et al. Mitochondrial pyruvate carrier function determines cell stemness and metabolic reprogramming in cancer cells. Oncotarget. 2017;8:46363–80.

  29. 29.

    Bricker DK, Taylor EB, Schell JC, et al. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science. 2012;337:96–100.

  30. 30.

    Bender T, Pena G, Martinou JC. Regulation of mitochondrial pyruvate uptake by alternative pyruvate carrier complexes. EMBO J. 2015;34:911–24.

  31. 31.

    Gu Y, Song Y, Liu Y. [Clinical characteristics and prognostic factors of pulmonary tuberculosis with concurrent lung cancer]. Zhonghua Yi Xue Za Zhi. 2014;94:2838–40.

  32. 32.

    Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38–47.

Download references

Acknowledgements

This project was supported by grants from the National Natural Science Foundation of China (Nos. 81372684 and 81230062).

Author information

Correspondence to Xiu-Wu Bian or Xiong-Fei Wu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplementary Figures

Supplementary Tables

Rebuttal letter

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6