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Article

Immediate and transient phosphorylation of the heat shock protein 27 initiates chemoresistance in prostate cancer cells

  • Authors:
    • Matthias B. Stope
    • Martin Weiss
    • Melanie Preuss
    • Andreas  Streitbörger
    • Christoph A. Ritter
    • Uwe Zimmermann
    • Reinhard Walther
    • Martin Burchardt
  • View Affiliations / Copyright

    Affiliations: Department of Urology, University Medicine Greifswald, Greifswald, Germany, Institute of Pharmacy, Ernst-Moritz-Arndt-University of Greifswald, Greifswald, Germany, Department of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany
  • Pages: 2380-2386
    |
    Published online on: September 17, 2014
       https://doi.org/10.3892/or.2014.3492
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Abstract

Drug resistance minimizes the effects of prostate cancer (PC) chemotherapy with docetaxel and is generally considered to be associated with the expression of heat shock protein (HSP) 27 including various cytoprotective pathways. In the present study, we investigated the effects of HSP27 phosphorylation on PC cell growth underlying docetaxel treatment. Cell counting revealed significantly reduced cell growth during docetaxel treatment as a result of both activation of mitogen-activated protein kinase p38 (MAPK p38) and protein kinase D1 (PKD1), and, most importantly, the overexpression of the phosphorylation-mimicking mutant HSP27-3D. Further analysis revealed a docetaxel-dependent induction of HSP27 accompanied by an initial phosphorylation and rapid dephosphorylation of the protein. Based on the data, we can conclude that phosphorylation of HSP27 protein is a crucial mechanism in the initiation of chemoresistance in PC. Moreover, the results indicate a key impact of HSP27 on viability and proliferation of PC cells underlying anticancer therapy. The protective function depends on the initial phosphorylation status of HSP27 and represents a putative co-therapeutic target to prevent chemoresistance during docetaxel therapy.
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1 

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T and Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 58:71–96. 2008. View Article : Google Scholar

2 

Hwang C: Overcoming docetaxel resistance in prostate cancer: a perspective review. Ther Adv Med Oncol. 4:329–340. 2012. View Article : Google Scholar : PubMed/NCBI

3 

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

4 

Haslbeck M and Buchner J: Chaperone function of sHsps. Prog Mol Subcell Biol. 28:37–59. 2002. View Article : Google Scholar

5 

Parcellier A, Brunet M, Schmitt E, Col E, Didelot C, Hammann A, Nakayama K, Nakayama KI, Khochbin S, Solary E and Garrido C: HSP27 favors ubiquitination and proteasomal degradation of p27Kip1 and helps S-phase re-entry in stressed cells. FASEB J. 20:1179–1181. 2006. View Article : Google Scholar : PubMed/NCBI

6 

Ischia J, Saad F and Gleave M: The promise of heat shock protein inhibitors in the treatment of castration resistant prostate cancer. Curr Opin Urol. 23:194–200. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Liu T, Guevara OE, Warburton RR, Hill NS, Gaestel M and Kayyali US: Modulation of HSP27 alters hypoxia-induced endothelial permeability and related signaling pathways. J Cell Physiol. 220:600–610. 2009. View Article : Google Scholar : PubMed/NCBI

8 

Tsuji F, Oh-hashi K and Kiuchi K: Differential effects of Akt pathway inhibitors on IL-1β-induced protein phosphorylation in human fibroblast-like synoviocytes. J Recept Signal Transduct Res. 32:22–28. 2012.

9 

Hassan S, Biswas MH, Zhang C, Du C and Balaji KC: Heat shock protein 27 mediates repression of androgen receptor function by protein kinase D1 in prostate cancer cells. Oncogene. 28:4386–4396. 2009. View Article : Google Scholar : PubMed/NCBI

10 

Evans IM, Britton G and Zachary IC: Vascular endothelial growth factor induces heat shock protein (HSP) 27 serine 82 phosphorylation and endothelial tubulogenesis via protein kinase D and independent of p38 kinase. Cell Signal. 20:1375–1384. 2008. View Article : Google Scholar : PubMed/NCBI

11 

Landry J, Lambert H, Zhou M, Lavoie JN, Hickey E, Weber LA and Anderson CW: Human HSP27 is phosphorylated at serines 78 and 82 by heat shock and mitogen-activated kinases that recognize the same amino acid motif as S6 kinase II. J Biol Chem. 267:794–803. 1992.PubMed/NCBI

12 

Stope MB, Schubert T, Staar D, Rönnau C, Streitbörger A, Kroeger N, Kubisch C, Zimmermann U, Walther R and Burchardt M: Effect of the heat shock protein HSP27 on androgen receptor expression and function in prostate cancer cells. World J Urol. 30:327–331. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Stope MB, Bradl J, Peters S, Streitbörger A, Weiss M, Zimmermann U, Walther R, Lillig CH and Burchardt M: Shortened isoforms of the androgen receptor are regulated by the cytoprotective heat-shock protein HSPB1 and the tumor-suppressive microRNA miR-1 in prostate cancer cells. Anticancer Res. 33:4921–4926. 2013.PubMed/NCBI

14 

Dokas LA, Malone AM, Williams FE, Nauli SM and Messer WS Jr: Multiple protein kinases determine the phosphorylated state of the small heat shock protein, HSP27, in SH-SY5Y neuroblastoma cells. Neuropharmacology. 61:12–24. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Kubisch C, Dimagno MJ, Tietz AB, Welsh MJ, Ernst SA, Brandt-Nedelev B, Diebold J, Wagner AC, Göke B, Williams JA and Schäfer C: Overexpression of heat shock protein Hsp27 protects against cerulein-induced pancreatitis. Gastroenterology. 127:275–286. 2004. View Article : Google Scholar : PubMed/NCBI

16 

Rocchi P, So A, Kojima S, Signaevsky M, Beraldi E, Fazli L, Hurtado-Coll A, Yamanaka K and Gleave M: Heat shock protein 27 increases after androgen ablation and plays a cytoprotective role in hormone-refractory prostate cancer. Cancer Res. 64:6595–6602. 2004. View Article : Google Scholar : PubMed/NCBI

17 

Cuenda A, Rouse J, Doza YN, Meier R, Cohen P, Gallagher TF, Young PR and Lee JC: SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett. 364:229–233. 1995. View Article : Google Scholar : PubMed/NCBI

18 

Kostenko S and Moens U: Heat shock protein 27 phosphorylation: kinases, phosphatases, functions and pathology. Cell Mol Life Sci. 66:3289–3307. 2009. View Article : Google Scholar : PubMed/NCBI

19 

Jaggi M, Rao PS, Smith DJ, Hemstreet GP and Balaji KC: Protein kinase C mu is down-regulated in androgen-independent prostate cancer. Biochem Biophys Res Commun. 307:254–260. 2003. View Article : Google Scholar : PubMed/NCBI

20 

Mak P, Jaggi M, Syed V, Chauhan SC, Hassan S, Biswas H and Balaji KC: Protein kinase D1 (PKD1) influences androgen receptor (AR) function in prostate cancer cells. Biochem Biophys Res Commun. 373:618–623. 2008. View Article : Google Scholar : PubMed/NCBI

21 

Syed V, Mak P, Du C and Balaji KC: β-catenin mediates alteration in cell proliferation, motility and invasion of prostate cancer cells by differential expression of E-cadherin and protein kinase D1. J Cell Biochem. 104:82–95. 2008.

22 

Di K, Wong YC and Wang X: Id-1 promotes TGF-β1-induced cell motility through HSP27 activation and disassembly of adherens junction in prostate epithelial cells. Exp Cell Res. 313:3983–3999. 2007.

23 

Zoubeidi A, Zardan A, Beraldi E, Fazli L, Sowery R, Rennie P, Nelson C and Gleave M: Cooperative interactions between androgen receptor (AR) and heat-shock protein 27 facilitate AR transcriptional activity. Cancer Res. 67:10455–10465. 2007. View Article : Google Scholar : PubMed/NCBI

24 

Xu Y, Diao Y, Qi S, Pan X, Wang Q, Xin Y, Cao X, Ruan J, Zhao Z, Luo L, Liu C and Yin Z: Phosphorylated Hsp27 activates ATM-dependent p53 signaling and mediates the resistance of MCF-7 cells to doxorubicin-induced apoptosis. Cell Signal. 25:1176–1185. 2013. View Article : Google Scholar : PubMed/NCBI

25 

Nakashima M, Adachi S, Yasuda I, Yamauchi T, Kawaguchi J, Itani M, Yoshioka T, Matsushima-Nishiwaki R, Hirose Y, Kozawa O and Moriwaki H: Phosphorylation status of heat shock protein 27 plays a key role in gemcitabine-induced apoptosis of pancreatic cancer cells. Cancer Lett. 313:218–225. 2011. View Article : Google Scholar : PubMed/NCBI

26 

Taba K, Kuramitsu Y, Ryozawa S, Yoshida K, Tanaka T, Maehara S, Maehara Y, Sakaida I and Nakamura K: Heat-shock protein 27 is phosphorylated in gemcitabine-resistant pancreatic cancer cells. Anticancer Res. 30:2539–2543. 2010.PubMed/NCBI

27 

Sakai A, Otani M, Miyamoto A, Yoshida H, Furuya E and Tanigawa N: Identification of phosphorylated serine-15 and -82 residues of HSPB1 in 5-fluorouracil-resistant colorectal cancer cells by proteomics. J Proteomics. 75:806–818. 2012. View Article : Google Scholar : PubMed/NCBI

28 

Mouratidis PX, Colston KW, Bartlett JB, Muller GW, Man HW, Stirling D and Dalgleish AG: Antiproliferative effects of CC-8062 and CC-8075 in pancreatic cancer cells. Pancreas. 38:78–84. 2009. View Article : Google Scholar : PubMed/NCBI

29 

Garrido C, Ottavi P, Fromentin A, Hammann A, Arrigo AP, Chauffert B and Mehlen P: HSP27 as a mediator of confluence-dependent resistance to cell death induced by anticancer drugs. Cancer Res. 57:2661–2667. 1997.PubMed/NCBI

30 

Maizels ET, Peters CA, Kline M, Cutler RE Jr, Shanmugam M and Hunzicker-Dunn M: Heat-schock protein-25/27 phosphorylation by the d isoform of protein kinase C. Biochem J. 332:703–712. 1998.PubMed/NCBI

31 

Clifton AD, Young PR and Cohen P: A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAPkinase-3 and their activation by cytokines and cellular stress. FEBS Lett. 392:209–214. 1996. View Article : Google Scholar : PubMed/NCBI

32 

Guo K, Liu Y, Zhou H, Dai Z, Zhang J, Sun R, Chen J, Sun Q, Lu W, Kang X and Chen P: Involvement of protein kinase C β-extracellular signal-regulating kinase1/2/p38 mitogen-activated protein kinase-heat shock protein 27 activation in hepatocellular carcinoma cell motility and invasion. Cancer Sci. 99:486–496. 2008.

33 

Suga H, Nakajima K, Shu E, Kanno Y, Hirade K, Ishisaki A, Matsuno H, Tanabe K, Takai S, Akamatsu S, Kato K, Oiso Y and Kozawa O: Possible involvement of phosphatidylinositol 3-kinase/Akt signal pathway in vasopressin-induced HSP27 phosphorylation in aortic smooth muscle A10 cells. Arch Biochem Biophys. 438:137–145. 2005. View Article : Google Scholar : PubMed/NCBI

34 

Yuan J and Rozengurt E: PKD, PKD2, and p38 MAPK mediate Hsp27 serine-82 phosphorylation induced by neurotensin in pancreatic cancer PANC-1 cells. J Cell Biochem. 103:648–662. 2008. View Article : Google Scholar : PubMed/NCBI

35 

Liu F, Gore AJ, Wilson JL and Korc M: DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine. PLoS One. 9:e849822014. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Stope MB, Weiss M, Preuss M, Streitbörger A, Ritter CA, Zimmermann U, Walther R and Burchardt M: Immediate and transient phosphorylation of the heat shock protein 27 initiates chemoresistance in prostate cancer cells. Oncol Rep 32: 2380-2386, 2014.
APA
Stope, M.B., Weiss, M., Preuss, M., Streitbörger, A., Ritter, C.A., Zimmermann, U. ... Burchardt, M. (2014). Immediate and transient phosphorylation of the heat shock protein 27 initiates chemoresistance in prostate cancer cells. Oncology Reports, 32, 2380-2386. https://doi.org/10.3892/or.2014.3492
MLA
Stope, M. B., Weiss, M., Preuss, M., Streitbörger, A., Ritter, C. A., Zimmermann, U., Walther, R., Burchardt, M."Immediate and transient phosphorylation of the heat shock protein 27 initiates chemoresistance in prostate cancer cells". Oncology Reports 32.6 (2014): 2380-2386.
Chicago
Stope, M. B., Weiss, M., Preuss, M., Streitbörger, A., Ritter, C. A., Zimmermann, U., Walther, R., Burchardt, M."Immediate and transient phosphorylation of the heat shock protein 27 initiates chemoresistance in prostate cancer cells". Oncology Reports 32, no. 6 (2014): 2380-2386. https://doi.org/10.3892/or.2014.3492
Copy and paste a formatted citation
x
Spandidos Publications style
Stope MB, Weiss M, Preuss M, Streitbörger A, Ritter CA, Zimmermann U, Walther R and Burchardt M: Immediate and transient phosphorylation of the heat shock protein 27 initiates chemoresistance in prostate cancer cells. Oncol Rep 32: 2380-2386, 2014.
APA
Stope, M.B., Weiss, M., Preuss, M., Streitbörger, A., Ritter, C.A., Zimmermann, U. ... Burchardt, M. (2014). Immediate and transient phosphorylation of the heat shock protein 27 initiates chemoresistance in prostate cancer cells. Oncology Reports, 32, 2380-2386. https://doi.org/10.3892/or.2014.3492
MLA
Stope, M. B., Weiss, M., Preuss, M., Streitbörger, A., Ritter, C. A., Zimmermann, U., Walther, R., Burchardt, M."Immediate and transient phosphorylation of the heat shock protein 27 initiates chemoresistance in prostate cancer cells". Oncology Reports 32.6 (2014): 2380-2386.
Chicago
Stope, M. B., Weiss, M., Preuss, M., Streitbörger, A., Ritter, C. A., Zimmermann, U., Walther, R., Burchardt, M."Immediate and transient phosphorylation of the heat shock protein 27 initiates chemoresistance in prostate cancer cells". Oncology Reports 32, no. 6 (2014): 2380-2386. https://doi.org/10.3892/or.2014.3492
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