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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
Lässer, C., Eldh, M., and Lötvall, J., Isolation and characterization of RNA-containing exosomes, J. Vis. Exp., 2012, vol. 59, p. e3037.
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.
Liang, Y., Liu, J., and Feng, Z., The regulation of cellular metabolism by tumor suppressor p53, Cell Biosci., 2013, vol. 3, p. 9.
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.
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.
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.
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.
Naryzhny, S.N., Blue Dry Western: simple, economic, informative, and fast way of immunodetection, Anal. Biochem., 2009, vol. 392, pp. 90–95.
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.
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.
Raposo, G. and Stoorvogel, W., Extracellular vesicles: exosomes, microvesicles, and friends, J. Cell Biol., 2013, vol. 200, pp. 373–383.
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.
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.
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.
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.
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.
Vousden, K.H. and Prives, C., Blinded by the light: the growing complexity of p53, Cell, 2009, vol. 137, pp. 413–431.
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.
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.
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.
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
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
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S1990519X18010030