Skip to main content
Log in

Exosomes Transfer p53 between Cells and Can Suppress Growth and Proliferation of p53-Negative Cells

Cell and Tissue Biology Aims and scope Submit manuscript

Abstract

Exosomes are nanosized vesicles that are secreted by many types of cells. We have found that exosomes secreted by HEK293 and HT-1080 can suppress growth and proliferation of p53-deficient cells. Upon overexpression of exogenous p53-GFP in HEK293 cells, we observed p53 protein in exosomes that were secreted by these cells. We also found endogenous p53 in exosomes that were secreted by HT-1080 cells with a higher level of p53 expression. We were able to detect endogenous p53 protein in exosomes that originated from human plasma and were transferred to p53-deficient cells. Our findings indicate that p53 protein can be transferred between cells and may play an important physiological role.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abels, E.R. and Breakefield, X.O., Introduction to extracellular vesicles: biogenesis, RNA cargo selection, content, release, and uptake, Cell Mol. Neurobiol., 2016, vol. 36, pp. 301–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adamczyk, K.A., Klein-Scory, S., Tehrani, M.M., Warnken, U., Schmiegel, W., Schnölzer, M., and Schwarte-Waldhoff, I., Characterization of soluble and exosomal forms of the EGFR released from pancreatic cancer cells, Life Sci., 2011, vol. 89, pp. 304–312.

    Article  CAS  PubMed  Google Scholar 

  • Alvarez-Erviti, L., Seow, Y., Yin, H., Betts, C., Lakhal, S., and Wood, M.J., Delivery of SiRNA to the mouse brain by systemic injection of targeted exosomes, Nat. Biotechnol., 2011, vol. 29, pp. 341–345.

    Article  CAS  PubMed  Google Scholar 

  • Gopal, S.K., Greening, D.W., Hanssen, E.G., Zhu, H.J., Simpson, R.J., and Mathias, R.A., Oncogenic epithelial cell-derived exosomes containing Rac1 and PAK2 induce angiogenesis in recipient endothelial cells, Oncotarget, 2016, vol. 7, pp. 19709–19722.

    PubMed  PubMed Central  Google Scholar 

  • Graner, M.W., Alzate, O., Dechkovskaia, A.M., Keene, J.D., Sampson, J.H., Mitchell, D.A., and Bigner, D.D., Proteomic and immunologic analyses of brain tumor exosomes, FASEB J., 2009, vol. 23, pp. 1541–1557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grange, C., Tapparo, M., Collino, F., Vitillo, L., Damasco, C., Deregibus, M.C., Tetta, C, Bussolati, B., and Camussi, G., Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche, Cancer Res., 2011, vol. 71, pp. 5346–5356.

    Article  CAS  PubMed  Google Scholar 

  • György, B., Szabó, T.G., Pásztói, M., Pál, Z., Misják, P., Aradi, B., László, V., Pállinger, E., Pap, E., Kittel, A., Nagy, G., Falus, A., and Buzás, E.I., Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles, Cell Mol. Life. Sci., 2011, vol. 68, pp. 2667–2688.

    Article  PubMed  PubMed Central  Google Scholar 

  • Haney, M.J., Klyachko, N.L., Zhao, Y., Gupta, R., Plotnikova, E.G., He, Z., Patel T., Piroyan, A., Sokolsky, M., Kabanov, A.V., and Batrakova, E.V., Exosomes as drug delivery vehicles for Parkinson’s disease therapy, J. Control. Release, 2015, vol. 207, pp. 18–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Higginbotham, J.N., Demory Beckler, M., Gephart, J.D., Franklin, J.L., Bogatcheva, G., Kremers, G.J., Piston, D.W., Ayers, G.D., McConnell, R.E., Tyska, M.J., and Coffey, R.J., Amphiregulin exosomes increase cancer cell invasion, Curr. Biol., 2011, vol. 21, pp. 779–786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hollstein, M., Rice, K., Greenblatt, M.S., Soussi, T., Fuchs, R., Sorlie, T., Hovig, E., Smith-Sorensen, B., Montesano, R., and Harris, C.C., Database of p53 gene somatic mutations in human tumors and cell lines, Nucleic Acids Res., 1994, vol. 22, pp. 3551–3555.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huang, S.H., Li, Y., Zhang, J., Rong, J., and Ye, S., Epidermal growth factor receptor-containing exosomes induce tumor-specific regulatory T cells, Cancer Invest., 2013, vol. 31, pp. 330–335.

    Article  CAS  PubMed  Google Scholar 

  • Jørgensen, M.M., Bæk, R., and Varming, K., Potentials and capabilities of the extracellular vesicle (EV) array, J. Extracell. Vesicles, 2015, vol. 4, p. 26048. doi 10.3402/jev.v4.26048

    Article  PubMed  Google Scholar 

  • Kalra, H., Simpson, R.J., Ji, H., Aikawa, E., Altevogt, P., Askenase, P., Bond, V.C., Borra`s, F.E., Breakefield, X., Budnik, V., Buzas, E., Camussi, G., Clayton, A., Cocucci, E., Falcon-Perez, J.M., Gabrielsson, S., Gho, Y.S., Gupta, D., Harsha, H.C., Hendrix, A., Hill, A.F., Inal, J.M., Jenster, G., Kramer-Albers, E.M., Lim, S.K., Llorente, A., Lotvall, J., Marcilla, A., Mincheva-Nilsson, L., Nazarenko, I., Nieuwland, R., Noltet, Hoen, E.N., Pandey, A., Patel, T., Piper, M.G., Pluchino, S., Prasad, T.S., Rajendran, L., Raposo, G., Record, M., Reid, G.E., Sanchez-Madrid, F., Schiffelers, R.M., Siljander, P., Stensballe, A., Stoorvogel, W., Taylor, D., Thery, C., Valadi, H., van, Balkom, B.W., Vazquez, J., Vidal, M., Wauben, M.H., Yanez-Mo, M., Zoeller, M., and Mathivanan, S., Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation, PLoS Biol., 2012, vol. 10, p. e1001450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keerthikumar, S., Chisanga, D., Ariyaratne, D. AI, Saffar, H., Anand, S., Zhao, K., Samuel, M., Pathan, M., Jois, M., Chilamkurti, N., Gangoda, L., and Mathivanan, S., ExoCarta: a web-based compendium of exosomal cargo, J. Mol. Biol., 2016, vol. 428, pp. 688–692.

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi, M., Salomon, C., Tapia, J., Illanes, S.E., Mitchell, M.D., and Rice, G.E., Ovarian cancer cell invasiveness is associated with discordant exosomal sequestration of Let-7 miRNA and miR-200, J. Transl. Med., 2014, vol. 12, p. 4.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kovalev, R.A., Shtam, T.A., Karelov, D.V., Burdakov, V.S., Volnitskiy, A.V., Makarov, E.M., and Filatov, M.V., Histone deacetylase inhibitors cause the TP53-dependent induction of p21/Waf1 in tumor cells carrying mutations in TP53, Cell Tiss. Biol., 2015, vol. 9, no. 3, pp. 191–197.

    Article  Google Scholar 

  • Lässer, C., Eldh, M., and Lötvall, J., Isolation and characterization of RNA-containing exosomes, J. Vis. Exp., 2012, vol. 59, p. e3037.

    Google Scholar 

  • Lespagnol, A., Duflaut, D., Beekman, C., Blanc, L., Fiucci, G., Marine, J.C., Vidal, M., Amson, R., and Telerman, A., Exosome secretion, including the DNA damageinduced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice, Cell Death. Differ., 2008, vol. 15, pp. 1723–1733.

    Article  CAS  PubMed  Google Scholar 

  • Liang, Y., Liu, J., and Feng, Z., The regulation of cellular metabolism by tumor suppressor p53, Cell Biosci., 2013, vol. 3, p. 9.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lim, J.W., Mathias, R.A., Kapp, E.A., Layton, M.J., Faux, M.C., Burgess, A.W., Ji, H., and Simpson, R.J., Restoration of full-length APC protein in SW480 colon cancer cells induces exosome-mediated secretion of DKK-4, Electrophoresis, 2012, vol. 33, pp. 1873–1880.

    Article  CAS  PubMed  Google Scholar 

  • Meckes, D.G., Shair, K.H., Marquitz, A.R., Kung, C.P., Edwards, R.H., and Raab-Traub, N., Human tumor virus utilizes exosomes for intercellular communication, Proc. Natl. Acad. Sci. U. S. A., 2010, vol. 107, pp. 20370–20375.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mukhopadhyay, U.K. and Mak, A.S., p53: is the guardian of the genome also a suppressor of cell invasion, Cell Cycle, 2009, vol. 8, p. 2481.

    Article  CAS  PubMed  Google Scholar 

  • Naghibalhossaini, F., Hosseini, H.M., Mokarram, P., and Zamani, M., High frequency of genes promoter methylation, but lack of BRAF V600E mutation among iranian colorectal cancer patients, Pathol. Oncol. Res., 2011, vol. 17, pp. 819–825.

    Article  CAS  PubMed  Google Scholar 

  • Naryzhny, S.N., Blue Dry Western: simple, economic, informative, and fast way of immunodetection, Anal. Biochem., 2009, vol. 392, pp. 90–95.

    Article  CAS  PubMed  Google Scholar 

  • Neubauer, A., He, M., Schmidt, C.A., Huhn, D., and Liu, E.T., Genetic alterations in the p53 gene in the blast crisis of chronic myelogenous leukemia: analysis by polymerase chain reaction based techniques, Leukemia, 1993, vol. 7, pp. 593–600.

    CAS  PubMed  Google Scholar 

  • Raimondo, F., Morosi, L., Chinello, C., Magni, F., and Pitto, M., Advances in membranous vesicle and exosome proteomics improving biological understanding and biomarker discovery, Proteomics, 2011, vol. 11, pp. 709–720.

    Article  CAS  PubMed  Google Scholar 

  • Raposo, G. and Stoorvogel, W., Extracellular vesicles: exosomes, microvesicles, and friends, J. Cell Biol., 2013, vol. 200, pp. 373–383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shtam, T.A., Kovalev, R.A., Varfolomeeva, E.Yu., Makarov, E.M., Kil, Yu.V., and Filatov, M.V., Exosomes are natural carriers of exogenous sirna to human cells in vitro, Cell Commun. Signal., 2013, vol. 11, p. 88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Soldevilla, B., Rodriguez, M., San, Millan, C., Garcia, V., Fernandez-Perianez, R., Gil-Calderon, B., Martin, P., Garcia-Grande, A., Silva, J., Bonilla, F., and Dominguez, G., Tumor-derived exosomes are enriched in DeltaNp73, which promotes oncogenic potential in acceptor cells and correlates with patient survival, Hum. Mol. Genet., 2014, vol. 3, pp. 467–478.

    Article  Google Scholar 

  • Srivastava, A., Babu, A., Filant, J., Moxley, K.M., Ruskin, R., Dhanasekaran, D., Sood, A.K., McMeekin, S., and Ramesh, R., Exploitation of exosomes as nanocarriers for gene-, chemo-, and immune-therapy of cancer, J. Biomed. Nanotechnol., 2016, vol. 12, pp. 1159–1173.

    Article  CAS  PubMed  Google Scholar 

  • Staubach, S., Razawi, H., and Hanisch, F.G., Proteomics of MUC1-containing lipid rafts from plasma membranes and exosomes of human breast carcinoma cells MCF-7, Proteomics, 2009, vol. 9, pp. 2820–2835.

    Article  CAS  PubMed  Google Scholar 

  • Ung, T.H., Madsen, H.J., Hellwinkel, J.E., Lencioni, A.M., and Graner, M.W., Exosome proteomics reveals transcriptional regulator proteins with potential to mediate downstream pathways, Cancer Sci., 2014, vol. 105, pp. 1384–1392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vousden, K.H. and Prives, C., Blinded by the light: the growing complexity of p53, Cell, 2009, vol. 137, pp. 413–431.

    Article  CAS  PubMed  Google Scholar 

  • Webber, J., Yeung, V., and Clayton, A., Extracellular vesicles as modulators of the cancer microenvironment, Semin. Cell Dev. Biol., 2015, vol. 40, pp. 27–34.

    Article  CAS  PubMed  Google Scholar 

  • You, B., Cao, X., Shao, X., Ni, H., Shi, S., Shan, Y., Gu, Z., and You, Y., Clinical and biological significance of HAX-1 overexpression in nasopharyngeal carcinoma, Oncotarget, 2016, vol. 7, pp. 12505–12524.

    PubMed  PubMed Central  Google Scholar 

  • Yu, X., Harris, S.L., and Levine, A.J., The regulation of exosome secretion: a novel function of the p53 protein, Cancer Res., 2006, vol. 66, pp. 4795–4801.

    Article  CAS  PubMed  Google Scholar 

  • Yu, S., Cao, H., Shen, B., and Feng, J., Tumor-derived exosomes in cancer progression and treatment failure, Oncotarget, 2015, vol. 6, pp. 37151–37168.

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. V. Filatov.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Burdakov, V.S., Kovalev, R.A., Pantina, R.A. et al. Exosomes Transfer p53 between Cells and Can Suppress Growth and Proliferation of p53-Negative Cells. Cell Tiss. Biol. 12, 20–26 (2018). https://doi.org/10.1134/S1990519X18010030

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1990519X18010030

Keywords

Navigation