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Examination of CK2α and NF-κB p65 expression in human benign prostatic hyperplasia and prostate cancer tissues

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Abstract

Protein kinase CK2 plays a critical role in cell growth, proliferation, and suppression of cell death. CK2 is overexpressed, especially in the nuclear compartment, in the majority of cancers, including prostate cancer (PCa). CK2-mediated activation of transcription factor nuclear factor kappa B (NF-κB) p65 is a key step in cellular proliferation, resulting in translocation of NF-κB p65 from the cytoplasm to the nucleus. As CK2 expression and activity are also elevated in benign prostatic hyperplasia (BPH), we sought to increase the knowledge of CK2 function in benign and malignant prostate by examination of the relationships between nuclear CK2 and nuclear NF-κB p65 protein expression. The expression level and localization of CK2α and NF-κB p65 proteins in PCa and BPH tissue specimens was determined. Nuclear CK2α and NF-κB p65 protein levels are significantly higher in PCa compared with BPH, and these proteins are positively correlated with each other in both diseases. Nuclear NF-κB p65 levels correlated with Ki-67 or with cytoplasmic NF-κB p65 expression in BPH, but not in PCa. The findings provide information that combined analysis of CK2α and NF-κB p65 expression in prostate specimens relates to the disease status. Increased nuclear NF-κB p65 expression levels in PCa specifically related to nuclear CK2α levels, indicating a possible CK2-dependent relationship in malignancy. In contrast, nuclear NF-κB p65 protein levels related to both Ki-67 and cytoplasmic NF-κB p65 levels exclusively in BPH, suggesting a potential separate impact for NF-κB p65 function in proliferation for benign disease as opposed to malignant disease.

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References

  1. Bian Y, Ye M, Wang C, Cheng K, Song C, Dong M, Pan Y, Qin H, Zou H (2013) Global screening of CK2 kinase substrates by an integrated phosphoproteomics workflow. Sci Rep 3:3460. doi:10.1038/srep03460

    Article  PubMed  PubMed Central  Google Scholar 

  2. Núñez de Villavicencio-Díaz T, Mazola Y, Perera Negrín Y, Cruz García Y, Guirola Cruz O, Perea Rodríguez SE (2015) Predicting CK2 beta-dependent substrates using linear patterns. Biochem Biophys Rep 4:20–27. doi:10.1016/j.bbrep.2015.08.011

    Google Scholar 

  3. Guerra B, Issinger OG (2008) Protein kinase CK2 in human diseases. Curr Med Chem 15(19):1870–1886. doi:10.1007/s00018-009-9148-9

    Article  CAS  PubMed  Google Scholar 

  4. Trembley JH, Wang G, Unger G, Slaton J, Ahmed K (2009) Protein kinase CK2 in health and disease: cK2: a key player in cancer biology. Cell Mol Life Sci 66(11–12):1858–1867. doi:10.1007/s00018-009-9154-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ruzzene M, Pinna LA (2010) Addiction to protein kinase CK2: a common denominator of diverse cancer cells? Biochim Biophys Acta 3:499–504. doi:10.1016/j.bbapap.2009.07.018

    Article  Google Scholar 

  6. Faust RA, Niehans G, Gapany M, Hoistad D, Knapp D, Cherwitz D, Davis A, Adams GL, Ahmed K (1999) Subcellular immunolocalization of protein kinase CK2 in normal and carcinoma cells. Int J Biochem Cell Biol 31(9):941–949. doi:10.1016/S1357-2725(99)00050-3

    Article  CAS  PubMed  Google Scholar 

  7. Giusiano S, Cochet C, Filhol O, Duchemin-Pelletier E, Secq V, Bonnier P, Carcopino X, Boubli L, Birnbaum D, Garcia S, Iovanna J, Charpin C (2011) Protein kinase CK2alpha subunit over-expression correlates with metastatic risk in breast carcinomas: quantitative immunohistochemistry in tissue microarrays. Eur J Cancer 47(5):792–801. doi:10.1016/j.ejca.2010.11.028

    Article  CAS  PubMed  Google Scholar 

  8. Mandal T, Bhowmik A, Chatterjee A, Chatterjee U, Chatterjee S, Ghosh MK (2014) Reduced phosphorylation of stat3 at Ser-727 mediated by casein kinase 2—protein phosphatase 2A enhances stat3 Tyr-705 induced tumorigenic potential of glioma cells. Cell Signal 26(8):1725–1734. doi:10.1016/j.cellsig.2014.04.003

    Article  CAS  PubMed  Google Scholar 

  9. Gapany M, Faust RA, Tawfic S, Davis A, Adams GL, Ahmed K (1995) Association of elevated protein kinase CK2 activity with aggressive behavior of squamous cell carcinoma of the head and neck. Mol Med 1(6):659–666

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Faust RA, Gapany M, Tristani P, Davis A, Adams GL, Ahmed K (1996) Elevated protein kinase CK2 activity in chromatin of head and neck tumors: association with malignant transformation. Cancer Lett 101(1):31–35. doi:10.1016/0304-3835(96)04110-9

    Article  CAS  PubMed  Google Scholar 

  11. Laramas M, Pasquier D, Filhol O, Ringeisen F, Descotes JL, Cochet C (2007) Nuclear localization of protein kinase CK2 catalytic subunit (CK2alpha) is associated with poor prognostic factors in human prostate cancer. Eur J Cancer 43(5):928–934. doi:10.1016/j.ejca.2006.11.021

    Article  CAS  PubMed  Google Scholar 

  12. Yenice S, Davis AT, Goueli SA, Akdas A, Limas C, Ahmed K (1994) Nuclear casein kinase 2 (CK-2) activity in human normal, benign hyperplastic, and cancerous prostate. Prostate 24(1):11–16

    Article  CAS  PubMed  Google Scholar 

  13. Wang D, Westerheide SD, Hanson JL, Baldwin AS (2000) Tumor necrosis factor α-induced phosphorylation of relA/p65 on Ser529 is controlled by casein kinase II. J Biol Chem 275(42):32592–32597

    Article  CAS  PubMed  Google Scholar 

  14. Barroga CF, Stevenson JK, Schwarz EM, Verma IM (1995) Constitutive phosphorylation of I kappa B alpha by casein kinase II. Proc Natl Acad Sci USA 92(17):7637–7641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Romieu-Mourez R, Landesman-Bollag E, Seldin DC, Traish AM, Mercurio F, Sonenshein GE (2001) Roles of IKK kinases and protein kinase CK2 in activation of nuclear factor-κB in breast cancer. Cancer Res 61(9):3810–3818

    CAS  PubMed  Google Scholar 

  16. Dominguez I, Sonenshein GE, Seldin DC (2009) Protein kinase CK2 in health and disease: cK2 and its role in Wnt and NF-kappaB signaling: linking development and cancer. Cell Mol Life Sci 66(11–12):1850–1857. doi:10.1007/s00018-009-9153-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hoesel B, Schmid JA (2013) The complexity of NF-kappaB signaling in inflammation and cancer. Mol Cancer 12:86. doi:10.1186/1476-4598-12-86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Suh J, Payvandi F, Edelstein LC, Amenta PS, Zong WX, Gelinas C, Rabson AB (2002) Mechanisms of constitutive NF-kappaB activation in human prostate cancer cells. Prostate 52(3):183–200. doi:10.1002/pros.10082

    Article  CAS  PubMed  Google Scholar 

  19. Brown M, Cohen J, Arun P, Chen Z, Van Waes C (2008) NF-kappaB in carcinoma therapy and prevention. Exp Opin Ther Targ 12(9):1109–1122. doi:10.1517/14728222.12.9.1109

    Article  CAS  Google Scholar 

  20. Nguyen DP, Li JY, Yadav SS, Tewari AK (2014) Recent insights into NF-kappa B signalling pathways and the link between inflammation and prostate cancer. BJU Int 114(2):168–176. doi:10.1111/bju.12488

    Article  CAS  PubMed  Google Scholar 

  21. Nunez C, Cansino JR, Bethencourt F, Perez-Utrilla M, Fraile B, Martinez-Onsurbe P, Olmedilla G, Paniagua R, Royuela M (2008) TNF/IL-1/NIK/NF-kappa B transduction pathway: a comparative study in normal and pathological human prostate (benign hyperplasia and carcinoma). Histopathology 53(2):166–176. doi:10.1111/j.1365-2559.2008.03092.x

    Article  CAS  PubMed  Google Scholar 

  22. Guo Z, Xing Z, Cheng X, Fang Z, Jiang C, Su J, Zhou Z, Xu Z, Holmberg A, Nilsson S, Liu Z (2015) Somatostatin derivate (smsDX) attenuates the TAM-stimulated proliferation, migration and invasion of prostate cancer via NF-kappaB regulation. PLoS One 10(5):e0124292. doi:10.1371/journal.pone.0124292

    Article  PubMed  PubMed Central  Google Scholar 

  23. MacKenzie L, McCall P, Hatziieremia S, Catlow J, Adams C, McArdle P, Seywright M, Tanahill C, Paul A, Underwood M, Mackay S, Plevin R, Edwards J (2012) Nuclear factor kappaB predicts poor outcome in patients with hormone-naive prostate cancer with high nuclear androgen receptor. Hum Pathol 43(9):1491–1500. doi:10.1016/j.humpath.2011.11.009

    Article  CAS  PubMed  Google Scholar 

  24. McCall P, Bennett L, Ahmad I, Mackenzie LM, Forbes IW, Leung HY, Sansom OJ, Orange C, Seywright M, Underwood MA, Edwards J (2012) NFkappaB signalling is upregulated in a subset of castrate-resistant prostate cancer patients and correlates with disease progression. Br J Cancer 107(9):1554–1563. doi:10.1038/bjc.2012.372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gannon PO, Lessard L, Stevens LM, Forest V, Begin LR, Minner S, Tennstedt P, Schlomm T, Mes-Masson AM, Saad F (2013) Large-scale independent validation of the nuclear factor-kappa B p65 prognostic biomarker in prostate cancer. Eur J Cancer 49(10):2441–2448. doi:10.1016/j.ejca.2013.02.026

    Article  CAS  PubMed  Google Scholar 

  26. Austin DC, Strand DW, Love HL, Franco OE, Jang A, Grabowska MM, Miller NL, Hameed O, Clark PE, Fowke JH, Matusik RJ, Jin RJ, Hayward SW (2016) NF-kappaB and androgen receptor variant expression correlate with human BPH progression. Prostate 76(5):491–511. doi:10.1002/pros.23140

    Article  CAS  PubMed  Google Scholar 

  27. Trembley JH, Unger GM, Korman VL, Abedin MJ, Nacusi LP, Vogel RI, Slaton JW, Kren BT, Ahmed K (2014) Tenfibgen ligand nanoencapsulation delivers bi-functional anti-CK2 RNAi oligomer to key sites for prostate cancer targeting using human xenograft tumors in mice. PLoS One. doi:10.1371/journal.pone.0109970

    PubMed  PubMed Central  Google Scholar 

  28. Unger GM, Kren BT, Korman VL, Kimbrough TG, Vogel RI, Ondrey FG, Trembley JH, Ahmed K (2014) Mechanism and efficacy of sub-50-nm tenfibgen nanocapsules for cancer cell-directed delivery of anti-CK2 RNAi to primary and metastatic squamous cell carcinoma. Mol Cancer Ther 13(8):2018–2029. doi:10.1158/1535-7163.MCT-14-0166-7163.MCT-14-0166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Romieu-Mourez R, Landesman-Bollag E, Seldin DC, Sonenshein GE (2002) Protein kinase CK2 promotes aberrant activation of nuclear factor-{kappa}B, transformed phenotype, and survival of breast cancer cells. Cancer Res 62(22):6770–6778

    CAS  PubMed  Google Scholar 

  30. Eddy SF, Guo S, Demicco EG, Romieu-Mourez R, Landesman-Bollag E, Seldin DC, Sonenshein GE (2005) Inducible I{kappa}B kinase/I{kappa}B kinase varepsilon expression is induced by CK2 and promotes aberrant nuclear factor-{kappa}B activation in breast cancer cells. Cancer Res 65(24):11375–11383. doi:10.1158/0008-5472.can-05-1602

    Article  CAS  PubMed  Google Scholar 

  31. Le Page C, Koumakpayi IH, Lessard L, Saad F, Mes-Masson AM (2005) Independent role of phosphoinositol-3-kinase (PI3 K) and casein kinase II (CK-2) in EGFR and Her-2-mediated constitutive NF-kappaB activation in prostate cancer cells. Prostate 65(4):306–315. doi:10.1002/pros.20291

    Article  PubMed  Google Scholar 

  32. DeLong ER, DeLong DM, Clarke-Pearson DL (1988) Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44(3):837–845

    Article  CAS  PubMed  Google Scholar 

  33. Fisher G, Yang ZH, Kudahetti S, Moller H, Scardino P, Cuzick J, Berney DM (2013) Prognostic value of Ki-67 for prostate cancer death in a conservatively managed cohort. Br J Cancer 108(2):271–277. doi:10.1038/bjc.2012.598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cbioportal. Sci Signal. doi:10.1126/scisignal.2004088

    Google Scholar 

  35. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cbio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404. doi:10.1158/2159-8290.cd-12-0095

    Article  PubMed  Google Scholar 

  36. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS (2010) Integrative genomic profiling of human prostate cancer. Cancer Cell 18:11–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cancer Genome Atlas Research Network (2015) The Molecular taxonomy of primary prostate cancer. Cell 163(4):1011–1025. doi:10.1016/j.cell.2015.10.025

    Article  Google Scholar 

  38. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, Montgomery B, Taplin ME, Pritchard CC, Attard G, Beltran H, Abida W, Bradley RK, Vinson J, Cao X, Vats P, Kunju LP, Hussain M, Feng FY, Tomlins SA, Cooney KA, Smith DC, Brennan C, Siddiqui J, Mehra R, Chen Y, Rathkopf DE, Morris MJ, Solomon SB, Durack JC, Reuter VE, Gopalan A, Gao J, Loda M, Lis RT, Bowden M, Balk SP, Gaviola G, Sougnez C, Gupta M, Yu EY, Mostaghel EA, Cheng HH, Mulcahy H, True LD, Plymate SR, Dvinge H, Ferraldeschi R, Flohr P, Miranda S, Zafeiriou Z, Tunariu N, Mateo J, Perez-Lopez R, Demichelis F, Robinson BD, Schiffman M, Nanus DM, Tagawa ST, Sigaras A, Eng KW, Elemento O, Sboner A, Heath EI, Scher HI, Pienta KJ, Kantoff P, de Bono JS, Rubin MA, Nelson PS, Garraway LA, Sawyers CL, Chinnaiyan AM (2015) Integrative clinical genomics of advanced prostate cancer. Cell 161(5):1215–1228. doi:10.1016/j.cell.2015.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Trembley JH, Unger GM, Gomez OC, Abedin J, Korman VL, Vogel RI, Niehans G, Kren BT, Ahmed K (2014) Tenfibgen-DMAT nanocapsule delivers CK2 inhibitor DMAT to prostate cancer xenograft tumors causing inhibition of cell proliferation. Mol Cell Pharmacol 6(2):15–25

    PubMed  PubMed Central  Google Scholar 

  40. Trembley JH, Unger GM, Tobolt DK, Korman VL, Wang G, Ahmad KA, Slaton JW, Kren BT, Ahmed K (2011) Systemic administration of antisense oligonucleotides simultaneously targeting CK2alpha and alpha’ subunits reduces orthotopic xenograft prostate tumors in mice. Mol Cell Biochem 356(1–2):21–35. doi:10.1007/s11010-011-0943-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ortega CE, Seidner Y, Dominguez I (2014) Mining CK2 in cancer. PLoS One 9(12):e115609. doi:10.1371/journal.pone.0115609

    Article  PubMed  PubMed Central  Google Scholar 

  42. Luo W, Yu W-D, Ma Y, Chernov M, Trump DL, Johnson CS (2013) Inhibition of protein kinase CK2 reduces Cyp24a1 expression and enhances 1,25-dihydroxyvitamin D3 antitumor activity in human prostate cancer cells. Cancer Res 73(7):2289–2297. doi:10.1158/0008-5472.can-12-4119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lessard L, Mes-Masson AM, Lamarre L, Wall L, Lattouf JB, Saad F (2003) NF-kappa B nuclear localization and its prognostic significance in prostate cancer. BJU Int 91(4):417–420

    Article  CAS  PubMed  Google Scholar 

  44. Endl E, Gerdes J (2000) The Ki-67 protein: fascinating forms and an unknown function. Exp Cell Res 257(2):231–237. doi:10.1006/excr.2000.4888

    Article  CAS  PubMed  Google Scholar 

  45. Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H (1984) Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 133(4):1710–1715

    CAS  PubMed  Google Scholar 

  46. Landberg G, Roos G (1993) Proliferating cell nuclear antigen and Ki-67 antigen expression in human haematopoietic cells during growth stimulation and differentiation. Cell Prolif 26(5):427–437

    Article  CAS  PubMed  Google Scholar 

  47. Sulik M, Maruszak K, Puchalska J, Misiukiewicz-Poć M (2011) Expression of Ki-67 as a proliferation marker in prostate cancer. Pol Ann Med 18(1):12–19

    Article  Google Scholar 

  48. Nicholson TM, Ricke WA (2011) Androgens and estrogens in benign prostatic hyperplasia: past, present and future. Differentiation 82(4–5):184–199. doi:10.1016/j.diff.2011.04.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lin-Tsai O, Clark PE, Miller NL, Fowke JH, Hameed O, Hayward SW, Strand DW (2014) Surgical intervention for symptomatic benign prostatic hyperplasia is correlated with expression of the AP-1 transcription factor network. Prostate 74(6):669–679. doi:10.1002/pros.22785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by United States Department of Veterans Affairs Merit Review Program Grant numbers I01BX001731 and I01BX003282, and by National Cancer Institute Grant number R01CA150182 (KA). National University of Sciences and Technology provided financial support under the Mega S&T scholarship fund for this work (FQ and SS). Armed Forces Institute of Pathology and Armed Forces Institute of Urology, Rawalpindi, provided technical assistance in the conduct of this work. The results shown here are in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/.

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Correspondence to Khalil Ahmed.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Fatima Qaiser and Janeen H. Trembley contributed equally.

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Qaiser, F., Trembley, J.H., Sadiq, S. et al. Examination of CK2α and NF-κB p65 expression in human benign prostatic hyperplasia and prostate cancer tissues. Mol Cell Biochem 420, 43–51 (2016). https://doi.org/10.1007/s11010-016-2765-3

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