Skip to main content
SpringerLink
Log in

Loss of Concurrent Regulation of the Expression of BIF-1, BAX, and Beclin-1 in Primary and Metastatic Melanoma

  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Melanoma is one of the most aggressive and drug-resistant cancers. Despite novel promising therapeutic strategies, the prognosis of metastatic melanoma patients remains poor and it is often associated with high relapse rates. Endophilin B1, also known as BIF-1, is a multifunctional protein involved in several biological processes such as autophagy and apoptosis. BIF-1 promotes apoptosis through binding to BAX and its translocation to the mitochondrial outer membrane. On the other hand, BIF-1 can interact with Beclin-1 through UVRAG to promote autophagy. Several reports suggest an ambiguous role of BIF-1 in cancer development and progression. For example, it has been demonstrated that the expression of BIF-1 is reduced in both primary and metastatic melanoma and that the reduction of BIF-1 expression is associated with reduced overall survival of melanoma patients. Here we show that the expression of Beclin-1 and active form of BAX are also reduced in the melanoma patients. However, while we observed strong positive correlations between the expression of BIF-1 and Beclin-1 as well as between BIF-1 and BAX in benign nevi, these correlations were lost in the primary and metastatic melanoma cells. These data indicate disruption in the proximal molecular mechanisms which regulate expression of BIF-1, Beclin-1, and BAX in the primary and metastatic melanoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.

Similar content being viewed by others

References

  1. Kjaerulff, O., Brodin, L., and Jung, A. (2011) The structure and function of endophilin proteins, Cell Biochem. Biophys., 60, 137-154, doi: https://doi.org/10.1007/s12013-010-9137-5.

    Article  CAS  Google Scholar 

  2. Frangez, Z., Fernandez-Marrero, Y., Stojkov, D., Seyed Jafari, S. M., Hunger, R. E., Djonov, V., Riether, C., and Simon, H. U. (2020) BIF-1 inhibits both mitochondrial and glycolytic ATP production: its downregulation promotes melanoma growth, Oncogene, 39, 4944-4955, doi: https://doi.org/10.1038/s41388-020-1339-8.

    Article  CAS  Google Scholar 

  3. Cuddeback, S. M., Yamaguchi, H., Komatsu, K., Miyashita, T., Yamada, M., Wu, C., Singh, S., and Wang, H. G. (2001) Molecular cloning and characterization of Bif-1. A novel Src homology 3 domain-containing protein that associates with Bax, J. Biol. Chem., 276, 20559-20565, doi: https://doi.org/10.1074/jbc.M101527200.

    Article  CAS  Google Scholar 

  4. Karbowski, M., Jeong, S. Y., and Youle, R. J. (2004) Endophilin B1 is required for the maintenance of mitochondrial morphology, J. Cell Biol., 166, 1027-1039, doi: https://doi.org/10.1083/jcb.200407046.

    Article  CAS  PubMed  Google Scholar 

  5. Farsad, K., Ringstad, N., Takei, K., Floyd, S. R., Rose, K., and De Camilli, P. (2001) Generation of high curvature membranes mediated by direct endophilin bilayer interactions, J. Cell Biol., 155, 193-200, doi: https://doi.org/10.1083/jcb.200107075.

    Article  CAS  PubMed  Google Scholar 

  6. Takahashi, Y., Karbowski, M., Yamaguchi, H., Kazi, A., Wu, J., Sebti, S. M., Youle, R. J., and Wang, H. G. (2005) Loss of Bif-1 suppresses Bax/Bak conformational change and mitochondrial apoptosis, Mol. Cell. Biol., 25, 9369-9382, doi: https://doi.org/10.1128/MCB.25.21.9369-9382.2005.

    Article  CAS  PubMed  Google Scholar 

  7. Takahashi, Y., Coppola, D., Matsushita, N., Cualing, H. D., Sun, M., et al. (2007) Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis, Nat. Cell Biol., 9, 1142-1151, doi: https://doi.org/10.1038/ncb1634.

    Article  CAS  PubMed  Google Scholar 

  8. Kim, S. Y., Oh, Y. L., Kim, K. M., Jeong, E. G., Kim, M. S., Yoo, N. J., and Lee, S. H. (2008) Decreased expression of Bax-interacting factor-1 (Bif-1) in invasive urinary bladder and gallbladder cancers, Pathology, 40, 553-557, doi: https://doi.org/10.1080/00313020802320440.

    Article  CAS  Google Scholar 

  9. Coppola, D., Khalil, F., Eschrich, S. A., Boulware, D., Yeatman, T., and Wang, H. G. (2008) Down-regulation of Bax-interacting factor-1 in colorectal adenocarcinoma, Cancer, 113, 2665-2670, doi: https://doi.org/10.1002/cncr.23892.

    Article  PubMed  Google Scholar 

  10. Fan, R., Miao, Y., Shan, X., Qian, H., Song, C., Wu, G., Chen, Y., and Zha, W. (2012) Bif-1 is overexpressed in hepatocellular carcinoma and correlates with shortened patient survival, Oncol. Lett., 3, 851-854, doi: https://doi.org/10.3892/ol.2012.562.

    Article  PubMed  Google Scholar 

  11. Liu, H., He, Z., Bode, P., Moch, H., and Simon, H. U. (2018) Downregulation of autophagy-related proteins 1, 5, and 16 in testicular germ cell tumors parallels lowered LC3B and elevated p62 levels, suggesting reduced basal autophagy, Front. Oncol., 8, 366, doi: https://doi.org/10.3389/fonc.2018.00366.

    Article  PubMed  Google Scholar 

  12. Liu, H., He, Z., von Rutte, T., Yousefi, S., Hunger, R. E., and Simon, H. U. (2013) Down-regulation of autophagy-related protein 5 (ATG5) contributes to the pathogenesis of early-stage cutaneous melanoma, Sci. Transl. Med., 5, 202ra123, doi: https://doi.org/10.1126/scitranslmed.3005864.

    Article  CAS  Google Scholar 

  13. Bankhead, P., Loughrey, M. B., Fernandez, J. A., Dombrowski, Y., McArt, D. G., et al. (2017) QuPath: Open source software for digital pathology image analysis, Sci. Rep., 7, 16878, doi: https://doi.org/10.1038/s41598-017-17204-5.

    Article  CAS  PubMed  Google Scholar 

  14. Yu, L., Chen, Y., and Tooze, S. A. (2018) Autophagy pathway: Cellular and molecular mechanisms, Autophagy, 14, 207-215, doi: https://doi.org/10.1080/15548627.2017.1378838.

    Article  CAS  Google Scholar 

  15. Tanida, I., Ueno, T., and Kominami, E. (2008) LC3 and Autophagy, Methods Mol. Biol., 445, 77-88, doi: https://doi.org/10.1007/978-1-59745-157-4_4.

    Article  CAS  Google Scholar 

  16. Sprecher, E., Bergman, R., Meilick, A., Kerner, H., Manov, L., Reiter, I., Shafer, Y., Maor, G., and Friedman-Birnbaum, R. (1999) Apoptosis, Fas and Fas-ligand expression in melanocytic tumors, J. Cutan. Pathol., 26, 72-77, doi: https://doi.org/10.1111/j.1600-0560.1999.tb01805.x.

    Article  CAS  Google Scholar 

  17. Mukhopadhyay, S., Panda, P. K., Sinha, N., Das, D. N., and Bhutia, S. K. (2014) Autophagy and apoptosis: where do they meet? Apoptosis, 19, 555-566, doi: https://doi.org/10.1007/s10495-014-0967-2.

    Article  CAS  Google Scholar 

  18. Nagata, S., and Tanaka, M. (2017) Programmed cell death and the immune system, Nat. Rev. Immunol., 17, 333-340, doi: https://doi.org/10.1038/nri.2016.153.

    Article  CAS  Google Scholar 

  19. Singh, R., Letai, A., and Sarosiek, K. (2019) Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins, Nat. Rev. Mol. Cell Biol., 20, 175-193, doi: https://doi.org/10.1038/s41580-018-0089-8.

    Article  CAS  PubMed  Google Scholar 

  20. Todt, F., Cakir, Z., Reichenbach, F., Emschermann, F., Lauterwasser, J., et al. (2015) Differential retrotranslocation of mitochondrial Bax and Bak, EMBO J., 34, 67-80, doi: https://doi.org/10.15252/embj.201488806.

    Article  CAS  PubMed  Google Scholar 

  21. Tait, S. W., and Green, D. R. (2010) Mitochondria and cell death: outer membrane permeabilization and beyond, Nat. Rev. Mol. Cell Biol., 11, 621-632, doi: https://doi.org/10.1038/nrm2952.

    Article  CAS  PubMed  Google Scholar 

  22. Guner, D., Sturm, I., Hemmati, P., Hermann, S., Hauptmann, S., et al. (2003) Multigene analysis of Rb pathway and apoptosis control in esophageal squamous cell carcinoma identifies patients with good prognosis, Int. J. Cancer, 103, 445-454, doi: https://doi.org/10.1002/ijc.10850.

    Article  CAS  PubMed  Google Scholar 

  23. Tai, Y. T., Lee, S., Niloff, E., Weisman, C., Strobel, T., and Cannistra, S. A. (1998) BAX protein expression and clinical outcome in epithelial ovarian cancer, J. Clin. Oncol., 16, 2583-2590, doi: https://doi.org/10.1200/JCO.1998.16.8.2583.

    Article  CAS  PubMed  Google Scholar 

  24. Friess, H., Lu, Z., Graber, H. U., Zimmermann, A., Adler, G., Korc, M., Schmid, R. M., and Buchler, M. W. (1998) bax, but not bcl-2, influences the prognosis of human pancreatic cancer, Gut, 43, 414-421, doi: https://doi.org/10.1136/gut.43.3.414.

    Article  CAS  PubMed  Google Scholar 

  25. Krajewski, S., Blomqvist, C., Franssila, K., Krajewska, M., Wasenius, V. M., Niskanen, E., Nordling, S., and Reed, J. C. (1995) Reduced expression of proapoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in women with metastatic breast adenocarcinoma, Cancer Res., 55, 4471-4478.

    CAS  PubMed  Google Scholar 

  26. Fecker, L. F., Geilen, C. C., Tchernev, G., Trefzer, U., Assaf, C., Kurbanov, B. M., Schwarz, C., Daniel, P. T., and Eberle, J. (2006) Loss of proapoptotic Bcl-2-related multidomain proteins in primary melanomas is associated with poor prognosis, J. Invest. Dermatol., 126, 1366-1371, doi: https://doi.org/10.1038/sj.jid.5700192.

    Article  CAS  PubMed  Google Scholar 

  27. Tchernev, G., and Orfanos, C. E. (2007) Downregulation of cell cycle modulators p21, p27, p53, Rb and proapoptotic Bcl-2-related proteins Bax and Bak in cutaneous melanoma is associated with worse patient prognosis: preliminary findings, J. Cutan. Pathol., 34, 247-256, doi: https://doi.org/10.1111/j.1600-0560.2006.00700.x.

    Article  PubMed  Google Scholar 

  28. Liang, X. H., Jackson, S., Seaman, M., Brown, K., Kempkes, B., Hibshoosh, H., and Levine, B. (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1, Nature, 402, 672-676, doi: https://doi.org/10.1038/45257.

    Article  CAS  PubMed  Google Scholar 

  29. Qu, X., Yu, J., Bhagat, G., Furuya, N., Hibshoosh, H., et al. (2003) Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene, J. Clin. Invest., 112, 1809-1820, doi: https://doi.org/10.1172/JCI20039.

    Article  CAS  PubMed  Google Scholar 

  30. Sivridis, E., Koukourakis, M. I., Mendrinos, S. E., Karpouzis, A., Fiska, A., Kouskoukis, C., and Giatromanolaki, A. (2011) Beclin-1 and LC3A expression in cutaneous malignant melanomas: a biphasic survival pattern for beclin-1, Melanoma Res., 21, 188-195, doi: https://doi.org/10.1097/CMR.0b013e328346612c.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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

Funding

This work was financially supported by the Swiss National Science Foundation (310030_184816 to H. U. S.) and by the European Union Horizon 2020 Research and Innovation Program (Marie Sklodowska-Curie grant no. 642295; MEL-PLEX). Images were acquired on equipment supported by the Microscopy Imaging Centre of the University of Bern.

Author information

Authors and Affiliations

  1. Institute of Pharmacology, University of Bern, 3010, Bern, Switzerland

    Ž. Frangež & H.-U. Simon

  2. Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, 3010, Bern, Switzerland

    S. M. Seyed Jafari & R. E. Hunger

  3. Department of Clinical Immunology and Allergology, Sechenov University, 119435, Moscow, Russia

    H.-U. Simon

Authors
  1. Ž. Frangež
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. M. Seyed Jafari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. E. Hunger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H.-U. Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H.-U. Simon.

Ethics declarations

The authors declare no conflict of interest in financial or any other sphere. All the procedures carried out in the research with participation of humans were in compliance with the ethical standards of the institutional and/or national ethics committee and with the Helsinki Declaration of 1964 and its subsequent changes or with comparable ethics standards. Informed voluntary consent was obtained from every participant of the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Frangež, Ž., Seyed Jafari, S.M., Hunger, R.E. et al. Loss of Concurrent Regulation of the Expression of BIF-1, BAX, and Beclin-1 in Primary and Metastatic Melanoma. Biochemistry Moscow 85, 1227–1234 (2020). https://doi.org/10.1134/S0006297920100107

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297920100107

Keywords

Search

Navigation