Rotaviruses infect cells by binding to specific cell surface molecules including gangliosides, heat shock protein cognate protein 70 (Hsc70), and some integrins. The characterization of cell surface receptors defining viral tropism is crucial for inhibiting entry into the normal cells or the cancer cells. In the present work, several tumor cell-adapted rotavirus isolates were tested for their interaction with some heat shock proteins (HSPs) present in the U-937 cells, derived from a human pleural effusion (histiocytic lymphoma monocyte). This interaction was examined by virus overlay protein-binding (VOPB), immunochemistry, immuno-dot blot assays, and flow cytometry. The results indicated that the rotavirus isolates studied were able to infect U937 cells by interacting with Hsp90, Hsp70, Hsp60, Hsp40, Hsc70, protein disulfide isomerase (PDI), and integrin β3, which are implicated in cellular proliferation, differentiation, and cancer development. Interestingly, these cellular proteins were found to be associated in lipid microdomains (rafts), facilitating in this way eventual sequential interactions of the rotavirus particles with the cell surface receptors. The rotavirus tropism for U937 cells through the use of these cell surface proteins made this rotavirus isolates an attractive target for the development of oncolytic strategies in the context of alternative and complementary treatment of cancer.

Department of Physiological Sciences Faculty of Medicine Universidad Nacional de Colombia Bogota D C Colombia

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Arias CF, Silva-Ayala D, López S (2015) Rotavirus entry: a deep journey into the cell with several exits. J Virol 89:890–893. https://doi.org/10.1128/JVI.01787-14 PubMed DOI

Breitbach CJ, Lichty BD, Bell JC (2016) Oncolytic viruses: therapeutics with an identity crisis. EBioMedicine 9:31–36. https://doi.org/10.1016/j.ebiom.2016.06.046 PubMed DOI PMC

Calderwood SK, Gong J (2016) Heat shock proteins promote cancer: it’s a protection racket. Trends Biochem Sci 41:311–323. https://doi.org/10.1016/j.tibs.2016.01.003 PubMed DOI PMC

Chatterjee S, Burns T (2017) Targeting heat shock proteins in cancer: a promising therapeutic approach. Int J Mol Sci 18:1978. https://doi.org/10.3390/ijms18091978 DOI PMC

Ciarlet M, Crawford SE, Cheng E, Blutt SE, Rice DA, Bergelson JM, Estes MK (2002) VLA-2 (α2β1) integrin promotes rotavirus entry into cells but is not necessary for rotavirus attachment. J Virol 76:1109–1123. https://doi.org/10.1128/jvi.76.3.1109-1123.2002 PubMed DOI PMC

Ciocca DR, Calderwood SK (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10:86–103. https://doi.org/10.1379/CSC-99r.1 PubMed DOI PMC

Elia G, Santoro MG (1994) Regulation of heat shock protein synthesis by quercetin in human erythroleukaemia cells. Biochem J 300(Pt 1):201–209. https://doi.org/10.1042/bj3000201 PubMed DOI PMC

Espejo RT, López S, Arias C (1981) Structural polypeptides of simian rotavirus SA11 and the effect of trypsin. J Virol 37:156–160 DOI

Gadelle D, Bocs C, Graille M, Forterre P (2005) Inhibition of archaeal growth and DNA topoisomerase VI activities by the Hsp90 inhibitor radicicol. Nucleic Acids Res 33:2310–2317. https://doi.org/10.1093/nar/gki526 PubMed DOI PMC

Gualtero DF, Guzmán F, Acosta O, Guerrero CA (2007) Amino acid domains 280–297 of VP6 and 531–554 of VP4 are implicated in heat shock cognate protein hsc70-mediated rotavirus infection. Arch Virol 152:2183–2196. https://doi.org/10.1007/s00705-007-1055-5 PubMed DOI

Guerrero CA, Acosta O (2016) Inflammatory and oxidative stress in rotavirus infection. World J Virol 5:38. https://doi.org/10.5501/wjv.v5.i2.38 PubMed DOI PMC

Guerrero CA, Bouyssounade D, Zarate S, Isa P, Lopez T, Espinosa R, Romero P, Mendez E, Lopez S, Arias CF (2002) Heat shock cognate protein 70 is involved in rotavirus cell entry. J Virol 76:4096–4102. https://doi.org/10.1128/JVI.76.8.4096-4102.2002 PubMed DOI PMC

Guerrero CA, Guerrero RA, Silva E, Acosta O, Barreto E (2016) Experimental adaptation of rotaviruses to tumor cell lines. PLoS One 11:e0147666. https://doi.org/10.1371/journal.pone.0147666 PubMed DOI PMC

Guerrero CA, Méndez E, Zárate S, Isa P, López S, Arias CF (2000) Integrin αvβ3 mediates rotavirus cell entry. Proc Natl Acad Sci 97:14644–14649. https://doi.org/10.1073/pnas.250299897 PubMed DOI PMC

Guerrero CA, Zárate S, Corkidi G, López S, Arias CF (2000) Biochemical characterization of rotavirus receptors in MA104 cells. J Virol 74:9362–9371. https://doi.org/10.1128/jvi.74.20.9362-9371.2000 PubMed DOI PMC

Hewish MJ, Takada Y, Coulson BS (2000) Integrins α2β1 and α4β1 can mediate SA11 rotavirus attachment and entry into cells. J Virol 74:228–236. https://doi.org/10.1128/jvi.74.1.228-236.2000 PubMed DOI PMC

Hill C, Carlisle R (2019) Achieving systemic delivery of oncolytic viruses. Expert Opin Drug Deliv 1–14. https://doi.org/10.1080/17425247.2019.1617269

Howells A, Marelli G, Lemoine NR, Wang Y (2017) Oncolytic viruses-interaction of virus and tumor cells in the battle to eliminate cancer. Front Oncol 7:195. https://doi.org/10.3389/fonc.2017.00195 PubMed DOI PMC

Jatella M (1999) Heat shock proteins as cellular lifeguard. Ann Med 31:261. https://doi.org/10.3109/07853899908995889 DOI

Jayawardena N, Burga LN, Poirier JT, Bostina M (2019) Virus–receptor interactions: structural insights for oncolytic virus development. Oncolytic Virotherapy 8:39. https://doi.org/10.2147/OV.S218494 PubMed DOI PMC

Jindadamrongwech S, Smith DR (2004) Virus overlay protein binding assay (VOPBA) reveals serotype specific heterogeneity of dengue virus binding proteins on HepG2 human liver cells. Intervirology 47:370. https://doi.org/10.1159/000080882 PubMed DOI

Kao CY, Yang PM, Wu MH, Huang CC, Lee YC, Lee KH (2016) Heat shock protein 90 is involved in the regulation of HMGA2-driven growth and epithelial-to-mesenchymal transition of colorectal cancer cells. PeerJ 4:e1683. https://doi.org/10.7717/peerj.1683 PubMed DOI PMC

Klimczak M, Biecek P, Zylicz A, Zylicz M (2019) Heat shock proteins create a signature to predict the clinical outcome in breast cancer. Sci Rep 9:7507. https://doi.org/10.1038/s41598-019-43556-1 PubMed DOI PMC

Lee E, Lee DH (2017) Emerging roles of protein disulfide isomerase in cancer. BMB Rep 50:401. https://doi.org/10.5483/bmbrep.2017.50.8.107 PubMed DOI PMC

Lin PH, Selinfreund R, Wakshull E, Wharton W (1987) Rapid and efficient purification of plasma membrane from cultured cells: characterization of epidermal growth factor binding. Biochemistry 26:731–736. https://doi.org/10.1021/bi00377a012 PubMed DOI

Liu T, Daniels CK, Cao S (2012) Comprehensive review on the HSC70 functions, interactions with related molecules and involvement in clinical diseases and therapeutic potential. Pharmacol Ther 136:354–374. https://doi.org/10.1016/j.pharmthera.2012.08.014 PubMed DOI PMC

Nahleh Z, Tfayli A, Najm A, El Sayed A, Nahle Z (2012) Heat shock proteins in cancer: targeting the ‘chaperones.’ Future Med Chem 4:927–935. https://doi.org/10.4155/fmc.12.50 PubMed DOI

Pan B, Guo J, Liao Q, Zhao Y (2018) β1 and β3 integrins in breast, prostate and pancreatic cancer: A novel implication. Oncol Lett 15:5412–5416. https://doi.org/10.3892/ol.2018.8076 PubMed DOI PMC

Pearl TM, Markert JM, Cassady KA, Ghonime MG (2019) Oncolytic virus-based cytokine expression to improve immune activity in brain and solid tumors. Mol Ther Oncolytics 13:14. https://doi.org/10.1016/j.omto.2019.03.001 PubMed DOI PMC

Raja J, Ludwig JM, Gettinger SN, Schalper KA, Kim HS (2018) Oncolytic virus immunotherapy: future prospects for oncology. J Immunother Cancer 6:140. https://doi.org/10.1186/s40425-018-0458-z PubMed DOI PMC

Rong Y, Yang EB, Zhang K, Mack P (2000) Quercetin-induced apoptosis in the monoblastoid cell line U937 in vitro and the regulation of heat shock proteins expression. Anticancer Res 20:4339–4345 PubMed

Samanta S, Tamura S, Dubeau L, Mhawech-Fauceglia P, Miyagi Y, Kato H, Lieberman R, Buckanovich RJ, Lin YG, Neamati N (2017) Expression of protein disulfide isomerase family members correlates with tumor progression and patient survival in ovarian cancer. Oncotarget 8:103543. https://doi.org/10.18632/oncotarget.21569

Santos TG, Martins V, Hajj G (2017) Unconventional secretion of heat shock proteins in cancer. Int J Mol Sci 18:946. https://doi.org/10.1371/journal.pone.0078443 DOI PMC

Schlecht R, Scholz SR, Dahmen H, Wegener A, Sirrenberg C, Musil D, Bomke J, Eggenweiler HM, Mayer MP, Bukau B (2013) Functional analysis of Hsp70 inhibitors. PLoS One 8:e78443. https://doi.org/10.1371/journal.pone.0078443 PubMed DOI PMC

Schneider-Schaulies J (2000) Cellular receptors for viruses: links to tropism and pathogenesis. J Gen Virol 81:1413–1429. https://doi.org/10.1371/journal.pone.0078443 PubMed DOI

Wu J, Liu T, Rios Z, Mei Q, Lin X, Cao S (2017) Heat shock proteins and cancer. Trends Pharmacol Sci 38:226–256. https://doi.org/10.1016/j.tips.2016.11.009 PubMed DOI

Xu S, Sankar S, Neamati N (2014) Protein disulfide isomerase: a promising target for cancer therapy. Drug Discov Today 19:222–240. https://doi.org/10.1016/j.drudis.2013.10.017 PubMed DOI

Yang R, Tang Q, Miao F, An Y, Li M, Han Y, Wang X, Wang J, Liu P, Chen R (2015) Inhibition of heat-shock protein 90 sensitizes liver cancer stem-like cells to magnetic hyperthermia and enhances anti-tumor effect on hepatocellular carcinoma-burdened nude mice. Int J Nanomedicine 10:7345–7358. https://doi.org/10.2147/IJN.S93758 PubMed DOI PMC

Zainutdinov SS, Kochneva GV, Netesov SV, Chumakov PM, Matveeva OV (2019) Directed evolution as a tool for the selection of oncolytic RNA viruses with desired phenotypes. Oncolytic Virotherapy 8:9. https://doi.org/10.2147/OV.S176523 PubMed DOI PMC

Zárate S, Cuadras MA, Espinosa R, Romero P, Juárez KO, Camacho-Nuez M, Arias CF, López S (2003) Interaction of rotaviruses with Hsc70 during cell entry is mediated by VP5. J Virol 77:7254–7260. https://doi.org/10.1128/JVI.77.13.7254-7260.2003 PubMed DOI PMC

Zárate S, Espinosa R, Romero P, Guerrero CA, Arias CF, López S (2000) Integrin α2β1 mediates the cell attachment of the rotavirus neuraminidase-resistant variant nar3. Virology 278:50–54. https://doi.org/10.1006/viro.2000.0660 PubMed DOI

Zárate S, Romero P, Espinosa R, Arias CF, López S (2004) VP7 mediates the interaction of rotaviruses with integrin αvβ3 through a novel integrin-binding site. J Virol 78:10839–10847. https://doi.org/10.1128/JVI.78.20.10839-10847.2004 PubMed DOI PMC