Hsp70 (HSP70A1A) downregulation enhances the metastatic ability of cancer cells

Kasioumi,Panagiota; Vrazeli,Paraskevi; Vezyraki,Patra; Zerikiotis,Stelios; Katsouras,Christos; Damalas,Alexander; Angelidis,Charalampos

doi:10.3892/ijo.2018.4666

Hsp70 (HSP70A1A) downregulation enhances the metastatic ability of cancer cells

Authors:
- Panagiota Kasioumi
- Paraskevi Vrazeli
- Patra Vezyraki
- Stelios Zerikiotis
- Christos Katsouras
- Alexander Damalas
- Charalampos Angelidis
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Affiliations: Department of General Biology, Michaelideion Cardiac Centre, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece, Department of General Biology, Michaelideion Cardiac Centre, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece, Department of Physiology, Michaelideion Cardiac Centre, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece, Department of Cardiology, Michaelideion Cardiac Centre, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece, Biotechnology and Nanomedicine Laboratory, University of Copenhagen, 2200 Copenhagen, Denmark
Published online on: December 12, 2018 https://doi.org/10.3892/ijo.2018.4666
Pages: 821-832
Copyright: © Kasioumi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Heat shock protein 70 (Hsp70; also known as HSP70A1A) is one of the most induced proteins in cancer cells; however, its role in cancer has not yet been fully elucidated. In the present study, we proposed a hypothetical model in which the silencing of Hsp70 enhanced the metastatic properties of the HeLa, A549 and MCF7 cancer cell lines. We consider that the inability of cells to form cadherin‑catenin complexes in the absence of Hsp70 stimulates their detachment from neighboring cells, which is the first step of anoikis and metastasis. Under these conditions, an epithelial‑to‑mesenchymal transition (EMT) pathway is activated that causes cancer cells to acquire a mesenchymal phenotype, which is known to possess a higher ability for migration. Therefore, we herein provide evidence of the dual role of Hsp70 which, according to international literature, first establishes a cancerous environment and then, as suggested by our team, regulates the steps of the metastatic process, including EMT and migration. Finally, the trigger for the anti‑metastatic properties that are acquired by cancer cells in the absence of Hsp70 appears to be the destruction of the Hsp70‑dependent heterocomplexes of E‑cadherin/catenins, which function like an anchor between neighboring cells.

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1	Murphy ME: The HSP70 family and cancer. Carcinogenesis. 34:1181–1188. 2013. View Article : Google Scholar : PubMed/NCBI
2	Lindquist S and Craig EA: The heat-shock proteins. Annu Rev Genet. 22:631–677. 1988. View Article : Google Scholar : PubMed/NCBI
3	Morimoto RI, Tissières A and Georgopoulos C: The stress response, function of the proteins, and perspectives. Stress Proteins in Biology and Medicine. Morimoto RI, Tissières A and Georgopoulos C: Cold Spring Harbor Laboratory Press, Cold Spring Harbor; New York: pp. 1–36. 1990
4	Hightower LE: Heat shock, stress proteins, chaperones, and proteotoxicity. Cell. 66:191–197. 1991. View Article : Google Scholar : PubMed/NCBI
5	Minami Y, Höhfeld J, Ohtsuka K and Hartl F-U: Regulation of the heat-shock protein 70 reaction cycle by the mammalian DnaJ homolog, Hsp40. J Biol Chem. 271:19617–19624. 1996. View Article : Google Scholar : PubMed/NCBI
6	Huang HC, Sherman MY, Kandror O and Goldberg AL: The molecular chaperone DnaJ is required for the degradation of a soluble abnormal protein in Escherichia coli. J Biol Chem. 276:3920–3928. 2001. View Article : Google Scholar
7	Bozidis P, Lazaridis I, Pagoulatos GN and Angelidis CE: Mydj2 as a potent partner of hsc70 in mammalian cells. Eur J Biochem. 269:1553–1560. 2002. View Article : Google Scholar : PubMed/NCBI
8	Angelidis CE, Lazaridis I and Pagoulatos GN: Aggregation of hsp70 and hsc70 in vivo is distinct and temperature-dependent and their chaperone function is directly related to non-aggregated forms. Eur J Biochem. 259:505–512. 1999. View Article : Google Scholar : PubMed/NCBI
9	Beckmann RP, Mizzen LE and Welch WJ: Interaction of Hsp 70 with newly synthesized proteins: Implications for protein folding and assembly. Science. 248:850–854. 1990. View Article : Google Scholar : PubMed/NCBI
10	Saliba RS, Munro PM, Luthert PJ and Cheetham ME: The cellular fate of mutant rhodopsin: Quality control, degradation and aggresome formation. J Cell Sci. 115:2907–2918. 2002.PubMed/NCBI
11	Chirico WJ, Waters MG and Blobel G: 70K heat shock related proteins stimulate protein translocation into microsomes. Nature. 332:805–810. 1988. View Article : Google Scholar : PubMed/NCBI
12	Kotoglou P, Kalaitzakis A, Vezyraki P, Tzavaras T, Michalis LK, Dantzer F, Jung JU and Angelidis C: Hsp70 translocates to the nuclei and nucleoli, binds to XRCC1 and PARP-1, and protects HeLa cells from single-strand DNA breaks. Cell Stress Chaperones. 14:391–406. 2009. View Article : Google Scholar :
13	Angelidis CE, Lazaridis I and Pagoulatos GN: Constitutive expression of heat-shock protein 70 in mammalian cells confers thermoresistance. Eur J Biochem. 199:35–39. 1991. View Article : Google Scholar : PubMed/NCBI
14	Angelidis C, Nova C, Lazaridis I, Kontoyiannis D, Kollias G and Pagoulatos GN: Overexpression of HSP70 in transgenic mice results in increased cell thermotolerance. Transgenics. 2:111–117. 1996.
15	Jäättelä M, Wissing D, Kokholm K, Kallunki T and Egeblad M: Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases. EMBO J. 17:6124–6134. 1998. View Article : Google Scholar : PubMed/NCBI
16	Damalas A, Velimezi G, Kalaitzakis A, Liontos M, Papavassiliou AG, Gorgoulis V and Angelidis C: Loss of p14(ARF) confers resistance to heat shock- and oxidative stress-mediated cell death by upregulating β-catenin. Int J Cancer. 128:1989–1995. 2011. View Article : Google Scholar
17	Cummings CJ, Cummings CJ, Sun Y, Opal P, Antalffy B, Mestril R, Orr HT, Dillmann WH and Zoghbi HY: Overexpression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum Mol Genet. 10:1511–1518. 2001. View Article : Google Scholar : PubMed/NCBI
18	Adachi H, Katsuno M, Minamiyama M, Sang C, Pagoulatos G, Angelidis C, Kusakabe M, Yoshiki A, Kobayashi Y, Doyu M, et al: Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein. J Neurosci. 23:2203–2211. 2003. View Article : Google Scholar : PubMed/NCBI
19	Scott MD and Frydman J: Aberrant protein folding as the molecular basis of cancer. Methods Mol Biol. 232:67–76. 2003.PubMed/NCBI
20	Mosser DD and Morimoto RI: Molecular chaperones and the stress of oncogenesis. Oncogene. 23:2907–2918. 2004. View Article : Google Scholar : PubMed/NCBI
21	Ammon-Treiber S, Grecksch G, Angelidis C, Vezyraki P, Höllt V and Becker A: Emotional and learning behaviour in mice over-expressing heat shock protein 70. Neurobiol Learn Mem. 90:358–364. 2008. View Article : Google Scholar : PubMed/NCBI
22	Plumier JC, Ross BM, Currie RW, Angelidis CE, Kazlaris H, Kollias G and Pagoulatos GN: Transgenic mice expressing the human heat shock protein 70 have improved post-ischemic myocardial recovery. J Clin Invest. 95:1854–1860. 1995. View Article : Google Scholar : PubMed/NCBI
23	Lysitsas DN, Katsouras CS, Papakostas JC, Toumpoulis IK, Angelidis C, Bozidis P, Thomas CG, Seferiadis K, Psychoyios N, Frillingos S, et al: Antirestenotic effects of a novel polymer-coated d-24851 eluting stent. Experimental data in a rabbit iliac artery model. Cardiovasc Intervent Radiol. 30:1192–1200. 2007. View Article : Google Scholar : PubMed/NCBI
24	Naka KK, Vezyraki P, Kalaitzakis A, Zerikiotis S, Michalis L and Angelidis C: Hsp70 regulates the doxorubicin-mediated heart failure in Hsp70-transgenic mice. Cell Stress Chaperones. 19:853–864. 2014. View Article : Google Scholar
25	Kyrou IE, Papakostas JC, Ioachim E, Koulouras V, Arnaoutoglou E, Angelidis C and Matsagkas MI: Early ischaemic preconditioning of spinal cord enhanced the binding profile of heat shock protein 70 with neurofilaments and promoted its nuclear translocation after thoraco-abdominal aortic occlusion in pigs. Eur J Vasc Endovasc Surg. 43:408–414. 2012. View Article : Google Scholar : PubMed/NCBI
26	Ninomiya H, Ohgami N, Oshino R, Kato M, Ohgami K, Li X, Shen D, Iida M, Yajima I, Angelidis CE, et al: Increased expression level of Hsp70 in the inner ears of mice by exposure to low frequency noise. Hear Res. 363:49–54. 2018. View Article : Google Scholar : PubMed/NCBI
27	Morano KA: New tricks for an old dog: The evolving world of Hsp70. Ann N Y Acad Sci. 1113:1–14. 2007. View Article : Google Scholar : PubMed/NCBI
28	Dudeja V, Mujumdar N, Phillips P, Chugh R, Borja-Cacho D, Dawra RK, Vickers SM and Saluja AK: Heat shock protein 70 inhibits apoptosis in cancer cells through simultaneous and independent mechanisms. Gastroenterology. 136:1772–1782. 2009. View Article : Google Scholar : PubMed/NCBI
29	Wei YQ, Zhao X, Kariya Y, Teshigawara K and Uchida A: Inhibition of proliferation and induction of apoptosis by abrogation of heat-shock protein (HSP) 70 expression in tumor cells. Cancer Immunol Immunother. 40:73–78. 1995. View Article : Google Scholar : PubMed/NCBI
30	Nylandsted J, Rohde M, Brand K, Bastholm L, Elling F and Jäättelä M: Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2. Proc Natl Acad Sci USA. 97:7871–7876. 2000. View Article : Google Scholar : PubMed/NCBI
31	Nylandsted J, Wick W, Hirt UA, Brand K, Rohde M, Leist M, Weller M and Jäättelä M: Eradication of glioblastoma, and breast and colon carcinoma xenografts by Hsp70 depletion. Cancer Res. 62:7139–7142. 2002.PubMed/NCBI
32	Frisch SM and Francis H: Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol. 124:619–626. 1994. View Article : Google Scholar : PubMed/NCBI
33	Guan JL and Shalloway D: Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature. 358:690–692. 1992. View Article : Google Scholar : PubMed/NCBI
34	Ruoslahti E and Reed JC: Anchorage dependence, integrins, and apoptosis. Cell. 77:477–478. 1994. View Article : Google Scholar : PubMed/NCBI
35	Jäättelä M: Escaping cell death: Survival proteins in cancer. Exp Cell Res. 248:30–43. 1999. View Article : Google Scholar : PubMed/NCBI
36	Beere HM, Wolf BB, Cain K, Mosser DD, Mahboubi A, Kuwana T, Tailor P, Morimoto RI, Cohen GM and Green DR: Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol. 2:469–475. 2000. View Article : Google Scholar : PubMed/NCBI
37	Kalluri R and Neilson EG: Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest. 112:1776–1784. 2003. View Article : Google Scholar : PubMed/NCBI
38	Peinado H, Olmeda D and Cano A: Snail, Zeb and bHLH factors in tumour progression: An alliance against the epithelial phenotype? Nat Rev Cancer. 7:415–428. 2007. View Article : Google Scholar : PubMed/NCBI
39	Huang RY, Guilford P and Thiery JP: Early events in cell adhesion and polarity during epithelial-mesenchymal transition. J Cell Sci. 125:4417–4422. 2012. View Article : Google Scholar : PubMed/NCBI
40	Yilmaz M and Christofori G: Mechanisms of motility in metastasizing cells. Mol Cancer Res. 8:629–642. 2010. View Article : Google Scholar : PubMed/NCBI
41	Yilmaz M and Christofori G, Yilmaz M and Christofori G: EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 28:15–33. 2009. View Article : Google Scholar : PubMed/NCBI
42	Niehrs C: The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol. 13:767–779. 2012. View Article : Google Scholar : PubMed/NCBI
43	Kourtidis A, Ngok SP and Anastasiadis PZ: p120 catenin: An essential regulator of cadherin stability, adhesion-induced signaling, and cancer progression. Prog Mol Biol Transl Sci. 116:409–432. 2013. View Article : Google Scholar : PubMed/NCBI
44	Hajra KM and Fearon ER: Cadherin and catenin alterations in human cancer. Genes Chromosomes Cancer. 34:255–268. 2002. View Article : Google Scholar : PubMed/NCBI
45	Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y and Johnson KR: Cadherin switching. J Cell Sci. 121:727–735. 2008. View Article : Google Scholar : PubMed/NCBI
46	Theveneau E and Mayor R: Cadherins in collective cell migration of mesenchymal cells. Curr Opin Cell Biol. 24:677–684. 2012. View Article : Google Scholar : PubMed/NCBI
47	Franke WW, Grund C, Kuhn C, Jackson BW and Illmensee K: Formation of cytoskeletal elements during mouse embryogenesis. III. Primary mesenchymal cells and the first appearance of vimentin filaments. Differentiation. 23:43–59. 1982. View Article : Google Scholar : PubMed/NCBI
48	McInroy L and Määttä A: Down-regulation of vimentin expression inhibits carcinoma cell migration and adhesion. Biochem Biophys Res Commun. 360:109–114. 2007. View Article : Google Scholar : PubMed/NCBI
49	Vuoriluoto K, Haugen H, Kiviluoto S, Mpindi JP, Nevo J, Gjerdrum C, Tiron C, Lorens JB and Ivaska J: Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene. 30:1436–1448. 2011. View Article : Google Scholar
50	Sun Y, Song GD, Sun N, Chen JQ and Yang SS: Slug overexpression induces stemness and promotes hepatocellular carcinoma cell invasion and metastasis. Oncol Lett. 7:1936–1940. 2014. View Article : Google Scholar : PubMed/NCBI
51	Angelidis CE, Lazaridis I and Pagoulatos GN: Specific inhibition of simian virus 40 protein synthesis by heat and arsenite treatment. Eur J Biochem. 172:27–34. 1988. View Article : Google Scholar : PubMed/NCBI
52	Doulias P-T, Kotoglou P, Tenopoulou M, Keramisanou D, Tzavaras T, Brunk U, Galaris D and Angelidis C: Involvement of heat shock protein-70 in the mechanism of hydrogen peroxide-induced DNA damage: The role of lysosomes and iron. Free Radic Biol Med. 42:567–577. 2007. View Article : Google Scholar : PubMed/NCBI
53	Gabai VL, Yaglom JA, Wang Y, Meng L, Shao H, Kim G, Colvin T, Gestwicki J and Sherman MY: Anti-cancer effects of targeting Hsp70 in tumor stromal cells. Cancer Res. 76:5926–5932. 2016. View Article : Google Scholar : PubMed/NCBI
54	Novak A and Dedhar S: Signaling through beta-catenin and Lef/Tcf. Cell Mol Life Sci. 56:523–537. 1999. View Article : Google Scholar
55	Chaw SY, Abdul Majeed A, Dalley AJ, Chan A, Stein S and Farah CS: Epithelial to mesenchymal transition (EMT) biomarkers - E-cadherin, beta-catenin, APC and Vimentin - in oral squamous cell carcinogenesis and transformation. Oral Oncol. 48:997–1006. 2012. View Article : Google Scholar : PubMed/NCBI
56	Mao J, Hu X, Xiao Y, Yang C, Ding Y, Hou N, Wang J, Cheng H and Zhang X: Overnutrition stimulates intestinal epithelium proliferation through β-catenin signaling in obese mice. Diabetes. 62:3736–3746. 2013. View Article : Google Scholar : PubMed/NCBI
57	Cowin P, Rowlands TM, Hatsell SJ and Cowin P: Rowlands TM and Hatsell SJ: Cadherins and Catenins in breast cancer. Curr Opin Cell Biol. 17:499–508. 2005. View Article : Google Scholar : PubMed/NCBI
58	Wu CY, Tsai YP, Wu MZ, Teng SC and Wu KJ: Epigenetic reprogramming and post-transcriptional regulation during the epithelial-mesenchymal transition. Trends Genet. 28:454–463. 2012. View Article : Google Scholar : PubMed/NCBI
59	Rodriguez LG, Wu X and Guan JL: Wound-healing assay. Methods Mol Biol. 294:23–29. 2005.
60	Ciocca DR and Calderwood SK: Heat shock proteins in cancer: Diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones. 10:86–103. 2005. View Article : Google Scholar : PubMed/NCBI
61	Garg M, Kanojia D, Seth A, Kumar R, Gupta A, Surolia A and Suri A: Heat-shock protein 70-2(HSP70-2) expression in bladder urothelial carcinoma is associated with tumour progression and promotes migration and invasion. Eur J Cancer. 46:207–215. 2010. View Article : Google Scholar
62	Teng Y, Ngoka L, Mei Y, Lesoon L and Cowell JK: HSP90 and HSP70 proteins are essential for stabilization and activation of WASF3 metastasis-promoting protein. J Biol Chem. 287:10051–10059. 2012. View Article : Google Scholar : PubMed/NCBI
63	Moreno-Bueno G, Peinado H, Molina P, Olmeda D, Cubillo E, Santos V, Palacios J, Portillo F and Cano A: The morphological and molecular features of the epithelial-to-mesenchymal transition. Nat Protoc. 4:1591–1613. 2009. View Article : Google Scholar : PubMed/NCBI
64	Buxton RS and Magee AI: Structure and interactions of desmosomal and other cadherins. Semin Cell Biol. 3:157–167. 1992. View Article : Google Scholar : PubMed/NCBI
65	Banh A, Deschamps PA, Vijayan MM, Sivak JG and West-Mays JA: The role of Hsp70 and Hsp90 in TGF-β-induced epithelial-to-mesenchymal transition in rat lens epithelial explants. Mol Vis. 13:2248–2262. 2007.PubMed/NCBI
66	Yun CH, Yoon SY, Nguyen TT, Cho HY, Kim TH, Kim ST, Kim BC, Hong YS, Kim SJ and Lee HJ: Geldanamycin inhibits TGF-β signaling through induction of Hsp70. Arch Biochem Biophys. 495:8–13. 2010. View Article : Google Scholar
67	Yang J, Zhu T, Liu X, Zhang L, Yang Y, Zhang J and Guο M: Heat shock protein 70 protects rat peritoneal mesothelial cells from advanced glycation end-products-induced epithelial-to-mesenchymal transition through mitogen activated protein kinases/extracellular signal-regulated kinases and transforming growth factor-β/Smad pathways. Mol Med Rep. 11:4473–4481. 2015. View Article : Google Scholar : PubMed/NCBI
68	Li Y, Kang X and Wang Q: HSP70 decreases receptor-dependent phosphorylation of Smad2 and blocks TGF-β-induced epithelial-mesenchymal transition. J Genet Genomics. 38:111–116. 2011. View Article : Google Scholar : PubMed/NCBI
69	Liu J, Bao J, Hao J, Peng Y and Hong F: HSP70 inhibits high glucose-induced Smad3 activation and attenuates epithelial-to-mesenchymal transition of peritoneal mesothelial cells. Mol Med Rep. 10:1089–1095. 2014. View Article : Google Scholar : PubMed/NCBI
70	Guarino M, Rubino B and Ballabio G: The role of epithelial-mesenchymal transition in cancer pathology. Pathology. 39:305–318. 2007. View Article : Google Scholar : PubMed/NCBI
71	Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, et al: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 133:704–715. 2008. View Article : Google Scholar : PubMed/NCBI
72	Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009. View Article : Google Scholar : PubMed/NCBI
73	Klymkowsky MW and Savagner P: Epithelial-mesenchymal transition: A cancer researcher's conceptual friend and foe. Am J Pathol. 174:1588–1593. 2009. View Article : Google Scholar : PubMed/NCBI
74	Thiery JP: Epithelial-mesenchymal transitions in cancer onset and progression. Bull Acad Natl Med. 193:1969–1979. 2009.In French.
75	Steeg PS: Targeting metastasis. Nat Rev Cancer. 16:201–218. 2016. View Article : Google Scholar : PubMed/NCBI
76	Qian CN, Mei Y and Zhang J: Cancer metastasis: Issues and challenges. Chin J Cancer. 36:382017. View Article : Google Scholar : PubMed/NCBI