Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

BIF-1 inhibits both mitochondrial and glycolytic ATP production: its downregulation promotes melanoma growth

Oncogene volume 39, pages 4944–4955 (2020)Cite this article

Subjects

Abstract

Endophilin B1, also known as BAX-interacting protein 1 (BIF-1), is part of the endophilin B protein family, and is a multifunctional protein involved in the regulation of apoptosis, autophagy, and mitochondrial morphology. The role of BIF-1 in cancer is controversial since previous reports indicated to both tumor-promoting and tumor-suppressive roles, perhaps depending on the cancer cell type. In the present study, we report that BIF-1 is significantly downregulated in both primary and metastatic melanomas, and that patients with high levels of BIF-1 expression exhibited a better overall survival. Depleting BIF-1 using CRISPR/Cas9 technology in melanoma cells resulted in higher proliferation rates both in vitro and in vivo, a finding that was associated with increased ATP production, metabolic acidification, and mitochondrial respiration. We also observed mitochondrial hyperpolarization, but no increase in the mitochondrial content of BIF-1-knockout melanoma cells. In contrast, such knockout melanoma cells were equally sensitive to anticancer drug- or UV irradiation-induced cell death, and exhibited similar autophagic activities as compared with control cells. Taken together, it appears that downregulation of BIF-1 contributes to tumorigenesis in cutaneous melanoma by upregulating mitochondrial respiration and metabolism, independent of its effect on apoptosis and autophagy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: BIF-1 expression is decreased in primary and metastatic melanomas compared with benign melanocytic nevi.
Fig. 2: BIF-1 limits proliferation of melanoma cells.
Fig. 3: BIF-1 inhibits mitochondrial metabolism.
Fig. 4: Lack of effect of autophagy on mitochondrial metabolism.
Fig. 5: BIF-1 negatively impacts the mitochondrial potential, length, and ROS production.

Similar content being viewed by others

References

  1. Kjaerulff O, Brodin L, Jung A. The structure and function of endophilin proteins. Cell Biochem Biophys. 2011;60:137–54.

    Article  CAS  Google Scholar 

  2. Giachino C, Lantelme E, Lanzetti L, Saccone S, Bella Valle G, Migone N. A novel SH3-containing human gene family preferentially expressed in the central nervous system. Genomics. 1997;41:427–34.

    Article  CAS  Google Scholar 

  3. Huttner WB, Schmidt A. Lipids, lipid modification and lipid-protein interaction in membrane budding and fission–insights from the roles of endophilin A1 and synaptophysin in synaptic vesicle endocytosis. Curr Opin Neurobiol. 2000;10:543–51.

    Article  CAS  Google Scholar 

  4. Masuda M, Takeda S, Sone M, Ohki T, Mori H, Kamioka Y, et al. Endophilin BAR domain drives membrane curvature by two newly identified structure-based mechanisms. EMBO J. 2006;25:2889–97.

    Article  CAS  Google Scholar 

  5. Farsad K, Ringstad N, Takei K, Floyd SR, Rose K, De Camilli P. Generation of high curvature membranes mediated by direct endophilin bilayer interactions. J Cell Biol. 2001;155:193–200.

    Article  CAS  Google Scholar 

  6. Loll PJ, Swain E, Chen Y, Turner BT, Zhang JF. Structure of the SH3 domain of rat endophilin A2. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2008;64:243–6.

    Article  CAS  Google Scholar 

  7. Takahashi Y, Coppola D, Matsushita N, Cualing HD, Sun M, Sato Y, et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol. 2007;9:1142–51.

    Article  CAS  Google Scholar 

  8. Pierrat B, Simonen M, Cueto M, Mestan J, Ferrigno P, Heim J. SH3GLB, a new endophilin-related protein family featuring an SH3 domain. Genomics. 2001;71:222–34.

    Article  CAS  Google Scholar 

  9. Cuddeback SM, Yamaguchi H, Komatsu K, Miyashita T, Yamada M, Wu C, et al. Molecular cloning and characterization of Bif-1. A novel Src homology 3 domain-containing protein that associates with Bax. J Biol Chem. 2001;276:20559–65.

    Article  CAS  Google Scholar 

  10. Takahashi Y, Karbowski M, Yamaguchi H, Kazi A, Wu J, Sebti SM, et al. Loss of Bif-1 suppresses Bax/Bak conformational change and mitochondrial apoptosis. Mol Cell Biol. 2005;25:9369–82.

    Article  CAS  Google Scholar 

  11. Karbowski M, Jeong SY, Youle RJ. Endophilin B1 is required for the maintenance of mitochondrial morphology. J Cell Biol. 2004;166:1027–39.

    Article  CAS  Google Scholar 

  12. Yamaguchi H, Woods NT, Dorsey JF, Takahashi Y, Gjertsen NR, Yeatman T, et al. SRC directly phosphorylates Bif-1 and prevents its interaction with Bax and the initiation of anoikis. J Biol Chem. 2008;283:19112–8.

    Article  CAS  Google Scholar 

  13. Schlauder SM, Calder KB, Khalil FK, Passmore L, Mathew RA, Morgan MB. Bif-1 and Bax expression in cutaneous Merkel cell carcinoma. J Cutan Pathol. 2009;36:21–25.

    Article  Google Scholar 

  14. Fan R, Miao Y, Shan X, Qian H, Song C, Wu G, et al. Bif-1 is overexpressed in hepatocellular carcinoma and correlates with shortened patient survival. Oncol Lett. 2012;3:851–4.

    PubMed  PubMed Central  Google Scholar 

  15. Kim SY, Oh YL, Kim KM, Jeong EG, Kim MS, Yoo NJ, et al. Decreased expression of Bax-interacting factor-1 (Bif-1) in invasive urinary bladder and gallbladder cancers. Pathology. 2008;40:553–7.

    Article  CAS  Google Scholar 

  16. Liu H, He Z, von Rutte T, Yousefi S, Hunger RE, Simon HU. Down-regulation of autophagy-related protein 5 (ATG5) contributes to the pathogenesis of early-stage cutaneous melanoma. Sci Transl Med. 2013;5:202ra123.

    Article  Google Scholar 

  17. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.

    Article  CAS  Google Scholar 

  18. Takahashi Y, Meyerkord CL, Hori T, Runkle K, Fox TE, Kester M, et al. Bif-1 regulates Atg9 trafficking by mediating the fission of Golgi membranes during autophagy. Autophagy. 2011;7:61–73.

    Article  CAS  Google Scholar 

  19. Rozman S, Yousefi S, Oberson K, Kaufmann T, Benarafa C, Simon HU. The generation of neutrophils in the bone marrow is controlled by autophagy. Cell Death Differ. 2015;22:445–56.

    Article  CAS  Google Scholar 

  20. Yang Z, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol. 2010;22:124–31.

    Article  CAS  Google Scholar 

  21. Mauthe M, Orhon I, Rocchi C, Zhou X, Luhr M, Hijlkema KJ, et al. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy. 2018;14:1435–55.

    Article  CAS  Google Scholar 

  22. Wang DB, Uo T, Kinoshita C, Sopher BL, Lee RJ, Murphy SP, et al. Bax interacting factor-1 promotes survival and mitochondrial elongation in neurons. J Neurosci. 2014;34:2674–83.

    Article  CAS  Google Scholar 

  23. Coppola D, Khalil F, Eschrich SA, Boulware D, Yeatman T, Wang HG. Down-regulation of Bax-interacting factor-1 in colorectal adenocarcinoma. Cancer. 2008;113:2665–70.

    Article  Google Scholar 

  24. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  Google Scholar 

  25. Xu L, Wang Z, He SY, Zhang SF, Luo HJ, Zhou K, et al. Bax-interacting factor-1 inhibits cell proliferation and promotes apoptosis in prostate cancer cells. Oncol Rep. 2016;36:3513–21.

    Article  CAS  Google Scholar 

  26. Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-Hernandez A, Saavedra E. Energy metabolism in tumor cells. FEBS J. 2007;274:1393–418.

    Article  CAS  Google Scholar 

  27. Weinberg SE, Chandel NS. Targeting mitochondria metabolism for cancer therapy. Nat Chem Biol. 2015;11:9–15.

    Article  CAS  Google Scholar 

  28. Jiao L, Zhang HL, Li DD, Yang KL, Tang J, Li X, et al. Regulation of glycolytic metabolism by autophagy in liver cancer involves selective autophagic degradation of HK2 (hexokinase 2). Autophagy. 2018;14:671–84.

    Article  CAS  Google Scholar 

  29. Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017;169:381–405.

    Article  CAS  Google Scholar 

  30. Mishra P, Chan DC. Metabolic regulation of mitochondrial dynamics. J Cell Biol. 2016;212:379–87.

    Article  CAS  Google Scholar 

  31. Koritzinsky M. Metformin: a novel biological modifier of tumor response to radiation therapy. Int J Radiat Oncol Biol Phys. 2015;93:454–64.

    Article  CAS  Google Scholar 

  32. Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife. 2014;3:e02242.

    Article  Google Scholar 

  33. Zannella VE, Dal Pra A, Muaddi H, McKee TD, Stapleton S, Sykes J, et al. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clin Cancer Res. 2013;19:6741–50.

    Article  CAS  Google Scholar 

  34. El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000;275:223–8.

    Article  CAS  Google Scholar 

  35. Diepart C, Karroum O, Magat J, Feron O, Verrax J, Calderon PB, et al. Arsenic trioxide treatment decreases the oxygen consumption rate of tumor cells and radiosensitizes solid tumors. Cancer Res. 2012;72:482–90.

    Article  CAS  Google Scholar 

  36. Simon N, Jolliet P, Morin C, Zini R, Urien SK, Tillement J-P. Glucocorticoids decrease cytochrome c oxidase activity of isolated rat kidney mitochondria. FEBS Lett. 1998;435:25–28.

    Article  CAS  Google Scholar 

  37. Bankhead P, Loughrey MB, Fernandez JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: open source software for digital pathology image analysis. Sci Rep. 2017;7:16878.

    Article  Google Scholar 

  38. Amini P, Stojkov D, Felser A, Jackson CB, Courage C, Schaller A, et al. Neutrophil extracellular trap formation requires OPA1-dependent glycolytic ATP production. Nat Commun. 2018;9:2958.

    Article  Google Scholar 

  39. Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol. 2005;174:6477–89.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Swiss National Science Foundation (310030_184816 to H.U.S.) and the European Union Horizon 2020 Research and Innovation Program (Marie Sklodowska-Curie grant No. 642295; MEL-PLEX). Ž.F. is a PhD student of the Graduate School of Cellular and Biomedical Sciences of the University of Bern. Images were acquired on equipment supported by the Microscopy Imaging Center of the University of Bern.

Author information

Authors and Affiliations

  1. Institute of Pharmacology, University of Bern, Bern, Switzerland

    Živa Frangež, Yuniel Fernández-Marrero, Darko Stojkov & Hans-Uwe Simon

  2. Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

    S. Morteza Seyed Jafari & Robert E. Hunger

  3. Institute of Anatomy, University of Bern, Bern, Switzerland

    Valentin Djonov

  4. Tumor Immunology, Department for Biomedical Research, University of Bern, Bern, Switzerland

    Carsten Riether

  5. Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

    Carsten Riether

  6. Department of Clinical Immunology and Allergology, Sechenov University, Moscow, Russia

    Hans-Uwe Simon

Authors
  1. Živa Frangež
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuniel Fernández-Marrero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Darko Stojkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Morteza Seyed Jafari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert E. Hunger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Valentin Djonov
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carsten Riether
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hans-Uwe Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Ž.F. conceived, planned, and performed the study, analyzed and interpreted data, and wrote the paper. Y.F.M., D.S., and S.M.S.J. performed the experiments; R.E.H. took clinical care of the melanoma patients; V.D. supported the electron microscopic analysis; C.R. supported the mouse experiments; H.U.S. provided overall guidance, experimental advice and laboratory infrastructure, and edited the paper; all authors read and approved the final paper.

Corresponding author

Correspondence to Hans-Uwe Simon.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Frangež, Ž., Fernández-Marrero, Y., Stojkov, D. et al. BIF-1 inhibits both mitochondrial and glycolytic ATP production: its downregulation promotes melanoma growth. Oncogene 39, 4944–4955 (2020). https://doi.org/10.1038/s41388-020-1339-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-020-1339-8

This article is cited by

Search

Advanced search

Quick links