Systemic administration of antisense oligonucleotides simultaneously targeting CK2α and α′ subunits reduces orthotopic xenograft prostate tumors in mice

  • Janeen H. Trembley
  • Gretchen M. Unger
  • Diane K. Tobolt
  • Vicci L. Korman
  • Guixia Wang
  • Kashif A. Ahmad
  • Joel W. Slaton
  • Betsy T. Kren
  • Khalil Ahmed
Article

Abstract

CK2 is a highly conserved, ubiquitous, signal responsive protein serine/threonine kinase. CK2 promotes cell proliferation and suppresses apoptosis, and increased CK2 expression is observed in all cancers examined. We previously reported that direct injection of antisense (AS) CK2α phosphorothioate oligonucleotides (PTO) into xenograft prostate tumors in mice significantly reduced tumor size. Downregulation of CK2α in tumor cells in vivo appeared to result in overexpression of CK2α′ protein. This suggested that in cancer cells downregulation of CK2α might be compensated by CK2α′ in vivo, prompting us to design a bispecific (bs) AS PTO (bs-AS-CK2) targeting both catalytic subunits. bs-AS-CK2 reduced CK2α and α′ protein expression, decreased cell proliferation, and induced apoptosis in cultured cells. Biodistribution studies of administered bs-AS-CK2 oligonucleotide demonstrated its presence in orthotopic prostate xenograft tumors. High dose injections of bs-AS-CK2 resulted in no damage to normal liver or prostate, but induced extensive cell death in tumor tissue. Intraperitoneal treatment with bs-AS-CK2 PTO decreased orthotopic tumor size and downregulated both CK2 mRNA and protein expression. Tumor reduction was accomplished using remarkably low doses and was improved by dividing the dose using a multi-day schedule. Decreased expression of the key signaling pathway proteins NF-κB p65 and AKT was also observed. We propose that the molecular downregulation of CK2 through bispecific targeting of the two catalytic subunits may be uniquely useful for therapeutic elimination of tumors.

Keywords

CK2 Prostate cancer Antisense NF-κB AKT Biodistribution 

Abbreviations

AS

Antisense

bs

Bispecific

CK2

Official acronym for former casein kinase 2 or II

CRPC

Castration-resistant prostate cancer

d

Day(s)

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

H&E

Hematoxylin and eosin stain

h

Hour(s)

HNSCC

Head and neck squamous cell carcinoma

i.p.

Intraperitoneal

i.v.

Intravenous

kDa

Kilo Dalton

LDH

Lactate dehydrogenase

min

Minutes

NF-κB

Nuclear factor kappa B

OGN

Oligonucleotide

PBS

Phosphate-buffered saline

PCa

Prostate cancer

PCR

Polymerase chain reaction

PKB

Protein kinase B

PTO

Phosphorothioate-modified oligodeoxynucleotide

RFP

Red fluorescent protein

s

Seconds

Ser

Serine

References

  1. 1.
    Ahmad KA, Wang G, Unger G, Slaton J, Ahmed K (2008) Protein kinase CK2–a key suppressor of apoptosis. Adv Enzyme Regul 48:179–187. doi:10.1016/j.advenzreg.2008.04.002 PubMedCrossRefGoogle Scholar
  2. 2.
    Pinna LA, Allende JE (2009) Protein kinase CK2 in health and disease: Protein kinase CK2: an ugly duckling in the kinome pond. Cell Mol Life Sci 66(11–12):1795–1799. doi:10.1007/s00018-009-9148-9 PubMedCrossRefGoogle Scholar
  3. 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 PubMedCrossRefGoogle Scholar
  4. 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 PubMedCrossRefGoogle Scholar
  5. 5.
    Trembley JH, Chen Z, Unger G, Slaton J, Kren BT, Van Waes C, Ahmed K (2010) Emergence of protein kinase CK2 as a key target in cancer therapy. BioFactors 36(3):187–195. doi:10.1002/biof.96 PubMedCrossRefGoogle Scholar
  6. 6.
    Salvi M, Sarno S, Cesaro L, Nakamura H, Pinna LA (2009) Extraordinary pleiotropy of protein kinase CK2 revealed by weblogo phosphoproteome analysis. Biochim Biophys Acta 1793(5):847–859. doi:10.1016/j.bbamcr.2009.01.013 PubMedCrossRefGoogle Scholar
  7. 7.
    Meggio F, Pinna LA (2003) One-thousand-and-one substrates of protein kinase CK2? FASEB J 17(3):349–368. doi:10.1096/fj.02-0473rev PubMedCrossRefGoogle Scholar
  8. 8.
    Graham KC, Litchfield DW (2000) The regulatory β subunit of protein kinase CK2 mediates formation of tetrameric CK2 complexes. J Biol Chem 275(7):5003–5010. doi:10.1074/jbc.275.7.5003 PubMedCrossRefGoogle Scholar
  9. 9.
    Zhang P, Davis AT, Ahmed K (1998) Mechanism of protein kinase CK2 association with nuclear matrix: role of disulfide bond formation. J Cell Biochem 69(2):211–220. doi:10.1002/(SICI)1097-4644(19980501)69:2<211:AID-JCB11>3.0.CO;2-H PubMedCrossRefGoogle Scholar
  10. 10.
    Tawfic S, Yu S, Wang H, Faust R, Davis A, Ahmed K (2001) Protein kinase CK2 signal in neoplasia. Histol Histopathol 16(2):573–582PubMedGoogle Scholar
  11. 11.
    Ahmed K, Davis AT, Wang H, Faust RA, Yu S, Tawfic S (2000) Significance of protein kinase CK2 nuclear signaling in neoplasia. J Cell Biochem Suppl 35:130–135. doi:10.1002/1097-4644(2000)79:35+<130:AID-JCB1136>3.0.CO;2-N PubMedCrossRefGoogle Scholar
  12. 12.
    Ahmed K (1999) Nuclear matrix and protein kinase CK2 signaling. Crit Rev Eukaryot Gene Expr 9(3–4):329–336PubMedGoogle Scholar
  13. 13.
    St-Denis NA, Litchfield DW (2009) Protein kinase CK2 in health and disease: From birth to death: the role of protein kinase CK2 in the regulation of cell proliferation and survival. Cell Mol Life Sci 66(11–12):1817–1829. doi:10.1007/s00018-009-9150-2 PubMedCrossRefGoogle Scholar
  14. 14.
    Ahmed K (1971) Studies on nuclear phosphoproteins of rat ventral prostate: incorporation of 32P from γ-32P-ATP. Biochim Biophys Acta 243:38–48Google Scholar
  15. 15.
    Ahmed K, Ishida H (1971) Effect of testosterone on nuclear phosphoproteins of rat ventral prostate. Mol Pharmacol 7(3):323–327PubMedGoogle Scholar
  16. 16.
    Guo C, Yu S, Davis AT, Ahmed K (1999) Nuclear matrix targeting of the protein kinase CK2 signal as a common downstream response to androgen or growth factor stimulation of prostate cancer cells. Cancer Res 59(5):1146–1151PubMedGoogle Scholar
  17. 17.
    Guo C, Yu S, Davis AT, Wang H, Green JE, Ahmed K (2001) A potential role of nuclear matrix-associated protein kinase CK2 in protection against drug-induced apoptosis in cancer cells. J Biol Chem 276(8):5992–5999. doi:10.1074/jbc.M004862200 PubMedCrossRefGoogle Scholar
  18. 18.
    Tawfic S, Faust RA, Gapany M, Ahmed K (1996) Nuclear matrix as an anchor for protein kinase CK2 nuclear signalling. J Cell Biochem 62(2):165–171. doi:10.1002/(SICI)1097-4644(199608)62:2<165:AID-JCB4>3.0.CO;2-Q PubMedCrossRefGoogle Scholar
  19. 19.
    Ahmed K, Yenice S, Davis A, Goueli SA (1993) Association of casein kinase 2 with nuclear chromatin in relation to androgenic regulation of rat prostate. Proc Natl Acad Sci USA 90(10):4426–4430PubMedCrossRefGoogle Scholar
  20. 20.
    Tawfic S, Goueli SA, Olson MO, Ahmed K (1994) Androgenic regulation of phosphorylation and stability of nucleolar protein nucleolin in rat ventral prostate. Prostate 24(2):101–106PubMedCrossRefGoogle Scholar
  21. 21.
    Tawfic S, Ahmed K (1994) Growth stimulus-mediated differential translocation of casein kinase 2 to the nuclear matrix. Evidence based on androgen action in the prostate. J Biol Chem 269(40):24615–24620PubMedGoogle Scholar
  22. 22.
    Yu S, Davis AT, Guo C, Green JE, Ahmed K (1999) Differential targeting of protein kinase CK2 to the nuclear matrix upon transient overexpression of its subunits. J Cell Biochem 74(1):127–134. doi:10.1002/(SICI)1097-4644(19990701)74:1<127:AID-JCB14>3.0.CO;2-3 PubMedCrossRefGoogle Scholar
  23. 23.
    Guo C, Davis AT, Ahmed K (1998) Dynamics of protein kinase CK2 association with nucleosomes in relation to transcriptional activity. J Biol Chem 273(22):13675–13680. doi:10.1074/jbc.273.22.13675 PubMedCrossRefGoogle Scholar
  24. 24.
    Yu S, Wang H, Davis A, Ahmed K (2001) Consequences of CK2 signaling to the nuclear matrix. Mol Cell Biochem 227(1–2):67–71. doi:10.1023/A:1013156721938 PubMedCrossRefGoogle Scholar
  25. 25.
    Elcock LS, Bridger JM (2008) Exploring the effects of a dysfunctional nuclear matrix. Biochem Soc Trans 36(Pt 6):1378–1383. doi:10.1042/BST0361378 PubMedCrossRefGoogle Scholar
  26. 26.
    Takahashi Y, Lallemand-Breitenbach V, Zhu J, de The H (2004) PML nuclear bodies and apoptosis. Oncogene 23(16):2819–2824. doi:10.1038/sj.onc.1207533 PubMedCrossRefGoogle Scholar
  27. 27.
    Slaton JW, Unger GM, Sloper DT, Davis AT, Ahmed K (2004) Induction of apoptosis by antisense CK2 in human prostate cancer xenograft model. Mol Cancer Res 2(12):712–721PubMedGoogle Scholar
  28. 28.
    Wang H, Davis A, Yu S, Ahmed K (2001) Response of cancer cells to molecular interruption of the CK2 signal. Mol Cell Biochem 227(1–2):167–174. doi:10.1023/A:1013112908734 PubMedCrossRefGoogle Scholar
  29. 29.
    Ahmad KA, Wang G, Slaton J, Unger G, Ahmed K (2005) Targeting CK2 for cancer therapy. Anticancer Drugs 16(10):1037–1043. doi:10.1097/00001813-200511000-00001 PubMedCrossRefGoogle Scholar
  30. 30.
    Rayan A, Goueli SA, Lange P, Ahmed K (1985) Chromatin-associated protein kinases in human normal and benign hyperplastic prostate. Cancer Res 45(5):2277–2282PubMedGoogle Scholar
  31. 31.
    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):11–16PubMedCrossRefGoogle Scholar
  32. 32.
    Ruzzene M, Pinna LA (2010) Addiction to protein kinase CK2: a common denominator of diverse cancer cells? Biochim Biophys Acta 1804(3):499–504. doi:10.1016/j.bbapap.2009.07.018 PubMedGoogle Scholar
  33. 33.
    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 PubMedCrossRefGoogle Scholar
  34. 34.
    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 PubMedCrossRefGoogle Scholar
  35. 35.
    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):659–666PubMedGoogle Scholar
  36. 36.
    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 (2010) Protein kinase CK2alpha subunit over-expression correlates with metastatic risk in breast carcinomas: quantitative immunohistochemistry in tissue microarrays. Eur J Cancer. doi:10.1016/j.ejca.2010.11.028
  37. 37.
    Laramas M, Pasquier D, Filhol O, Ringeisen F, Descotes JL, Cochet C (2007) Nuclear localization of protein kinase CK2 catalytic subunit (CK2α) 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 PubMedCrossRefGoogle Scholar
  38. 38.
    O-charoenrat P, Rusch V, Talbot SG, Sarkaria I, Viale A, Socci N, Ngai I, Rao P, Singh B (2004) Casein kinase II alpha subunit and C1-inhibitor are independent predictors of outcome in patients with squamous cell carcinoma of the lung. Clin Cancer Res 10(17):5792–5803. doi:10.1158/1078-0432.CCR-03-0317 PubMedCrossRefGoogle Scholar
  39. 39.
    Kim JS, Eom JI, Cheong J-W, Choi AJ, Lee JK, Yang WI, Min YH (2007) Protein kinase CK2α as an unfavorable prognostic marker and novel therapeutic target in acute myeloid leukemia. Clin Cancer Res 13(3):1019–1028. doi:10.1158/1078-0432.ccr-06-1602 PubMedCrossRefGoogle Scholar
  40. 40.
    Lin KY, Fang CL, Chen Y, Li CF, Chen SH, Kuo CY, Tai C, Uen YH (2010) Overexpression of nuclear protein kinase CK2 Beta subunit and prognosis in human gastric carcinoma. Ann Surg Oncol 17(6):1695–1702. doi:10.1245/s10434-010-0911-9 PubMedCrossRefGoogle Scholar
  41. 41.
    Lin KY, Tai C, Hsu JC, Li CF, Fang CL, Lai HC, Hseu YC, Lin YF, Uen YH (2011) Overexpression of nuclear protein kinase CK2 alpha catalytic subunit (CK2alpha) as a poor prognosticator in human colorectal cancer. PLoS One 6(2):e17193. doi:10.1371/journal.pone.0017193 PubMedCrossRefGoogle Scholar
  42. 42.
    McKenzie S, Kyprianou N (2006) Apoptosis evasion: the role of survival pathways in prostate cancer progression and therapeutic resistance. J Cell Biochem 97(1):18–32. doi:10.1002/jcb.20634 PubMedCrossRefGoogle Scholar
  43. 43.
    Ahmed K, Gerber DA, Cochet C (2002) Joining the cell survival squad: an emerging role for protein kinase CK2. Trends Cell Biol 12(5):226–230. doi:10.1016/S0962-8924(02)02279-1 PubMedCrossRefGoogle Scholar
  44. 44.
    Kelliher MA, Seldin DC, Leder P (1996) Tal-1 induces T cell acute lymphoblastic leukemia accelerated by casein kinase IIα. EMBO J 15(19):5160–5166PubMedGoogle Scholar
  45. 45.
    Landesman-Bollag E, Channavajhala PL, Cardiff RD, Seldin DC (1998) p53 deficiency and misexpression of protein kinase CK2α collaborate in the development of thymic lymphomas in mice. Oncogene 16(23):2965–2974. doi:10.1038/sj.onc.1201854 PubMedCrossRefGoogle Scholar
  46. 46.
    Landesman-Bollag E, Romieu-Mourez R, Song DH, Sonenshein GE, Cardiff RD, Seldin DC (2001) Protein kinase CK2 in mammary gland tumorigenesis. Oncogene 20(25):3247–3257. doi:10.1038/sj.onc.1204411 PubMedCrossRefGoogle Scholar
  47. 47.
    Landesman-Bollag E, Song DH, Romieu-Mourez R, Sussman DJ, Cardiff RD, Sonenshein GE, Seldin DC (2001) Protein kinase CK2: signaling and tumorigenesis in the mammary gland. Mol Cell Biochem 227(1–2):153–165. doi:10.1023/A:1013108822847 PubMedCrossRefGoogle Scholar
  48. 48.
    Channavajhala P, Seldin DC (2002) Functional interaction of protein kinase CK2 and c-Myc in lymphomagenesis. Oncogene 21(34):5280–5288. doi:10.1038/sj.onc.1205640 PubMedCrossRefGoogle Scholar
  49. 49.
    Hung MS, Lin YC, Mao JH, Kim IJ, Xu Z, Yang CT, Jablons DM, You L (2010) Functional polymorphism of the CK2alpha intronless gene plays oncogenic roles in lung cancer. PLoS One 5(7):e11418. doi:10.1371/journal.pone.0011418 PubMedCrossRefGoogle Scholar
  50. 50.
    Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, O’Brien SE, Bliesath J, Omori M, Huser N, Ho C, Proffitt C, Schwaebe MK, Ryckman DM, Rice WG, Anderes K (2010) CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res 70(24):10288–10298. doi:10.1158/0008-5472.can-10-1893 PubMedCrossRefGoogle Scholar
  51. 51.
    Perea SE, Reyes O, Puchades Y, Mendoza O, Vispo NS, Torrens I, Santos A, Silva R, Acevedo B, Lopez E, Falcon V, Alonso DF (2004) Antitumor effect of a novel proapoptotic peptide that impairs the phosphorylation by the protein kinase 2 (casein kinase 2). Cancer Res 64(19):7127–7129. doi:10.1158/0008-5472.CAN-04-2086 PubMedCrossRefGoogle Scholar
  52. 52.
    Perea SE, Reyes O, Baladron I, Perera Y, Farina H, Gil J, Rodriguez A, Bacardi D, Marcelo JL, Cosme K, Cruz M, Valenzuela C, Lopez-Saura PA, Puchades Y, Serrano JM, Mendoza O, Castellanos L, Sanchez A, Betancourt L, Besada V, Silva R, Lopez E, Falcon V, Hernandez I, Solares M, Santana A, Diaz A, Ramos T, Lopez C, Ariosa J, Gonzalez LJ, Garay H, Gomez D, Gomez R, Alonso DF, Sigman H, Herrera L, Acevedo B (2008) CIGB-300, a novel proapoptotic peptide that impairs the CK2 phosphorylation and exhibits anticancer properties both in vitro and in vivo. Mol Cell Biochem 316(1–2):163–167. doi:10.1007/s11010-008-9814-5 PubMedCrossRefGoogle Scholar
  53. 53.
    Perera Y, Farina HG, Hernandez I, Mendoza O, Serrano JM, Reyes O, Gomez DE, Gomez RE, Acevedo BE, Alonso DF, Perea SE (2008) Systemic administration of a peptide that impairs the protein kinase (CK2) phosphorylation reduces solid tumor growth in mice. Int J Cancer 122(1):57–62. doi:10.1002/ijc.23013 PubMedCrossRefGoogle Scholar
  54. 54.
    Solares AM, Santana A, Baladron I, Valenzuela C, Gonzalez CA, Diaz A, Castillo D, Ramos T, Gomez R, Alonso DF, Herrera L, Sigman H, Perea SE, Acevedo BE, Lopez-Saura P (2009) Safety and preliminary efficacy data of a novel casein kinase 2 (CK2) peptide inhibitor administered intralesionally at four dose levels in patients with cervical malignancies. BMC Cancer 9:146. doi:10.1186/1471-2407-9-146 PubMedCrossRefGoogle Scholar
  55. 55.
    Brown MS, Diallo OT, Hu M, Ehsanian R, Yang X, Arun P, Lu H, Korman V, Unger G, Ahmed K, Van Waes C, Chen Z (2010) CK2 modulation of NF-κB, TP53, and the malignant phenotype in head and neck cancer by anti-CK2 oligonucleotides in vitro or in vivo via sub-50-nm nanocapsules. Clin Cancer Res 16(8):2295–2307. doi:10.1158/1078-0432.ccr-09-3200 PubMedCrossRefGoogle Scholar
  56. 56.
    Pettaway CA, Pathak S, Greene G, Ramirez E, Wilson MR, Killion JJ, Fidler IJ (1996) Selection of highly metastatic variants of different human prostatic carcinomas using orthotopic implantation in nude mice. Clin Cancer Res 2(9):1627–1636PubMedGoogle Scholar
  57. 57.
    Hayward S, Dahiya R, Cunha G, Bartek J, Deshpande N, Narayan P (1995) Establishment and characterization of an immortalized but non-transformed human prostate epithelial cell line: BPH-1. In Vitro Cell Dev Biol Anim 31(1):14–24. doi:10.1007/BF02631333 PubMedCrossRefGoogle Scholar
  58. 58.
    Yamane K, Kinsella TJ (2005) CK2 inhibits apoptosis and changes its cellular localization following ionizing radiation. Cancer Res 65(10):4362–4367. doi:10.1158/0008-5472.CAN-04-3941 PubMedCrossRefGoogle Scholar
  59. 59.
    Ulloa L, Diaz-Nido J, Avila J (1993) Depletion of casein kinase II by antisense oligonucleotide prevents neuritogenesis in neuroblastoma cells. EMBO J 12(4):1633–1640PubMedGoogle Scholar
  60. 60.
    Fukuhara Y, Takeshima T, Kashiwaya Y, Shimoda K, Ishitani R, Nakashima K (2001) GAPDH knockdown rescues mesencephalic dopaminergic neurons from MPP+-induced apoptosis. Neuroreport 12(9):2049–2052PubMedCrossRefGoogle Scholar
  61. 61.
    Gaur U, Sahoo SK, De TK, Ghosh PC, Maitra A, Ghosh PK (2000) Biodistribution of fluoresceinated dextran using novel nanoparticles evading reticuloendothelial system. Int J Pharm 202(1–2):1–10. doi:10.1016/S0378-5173(99)00447-0 PubMedCrossRefGoogle Scholar
  62. 62.
    Son YJ, Jang JS, Cho YW, Chung H, Park RW, Kwon IC, Kim IS, Park JY, Seo SB, Park CR, Jeong SY (2003) Biodistribution and anti-tumor efficacy of doxorubicin loaded glycol-chitosan nanoaggregates by EPR effect. J Control Release 91(1–2):135–145. doi:10.1016/S0168-3659(03)00231-1 PubMedCrossRefGoogle Scholar
  63. 63.
    Ahmed RL, Davis AT, Ahmed K (1996) Interference in protein assays of biological specimens by vanadyl compounds. Anal Biochem 237(1):76–79. doi:10.1006/abio.1996.0203 PubMedCrossRefGoogle Scholar
  64. 64.
    Goueli SA, Hanten J, Davis A, Ahmed K (1990) Polyclonal antibodies against rat liver cytosolic casein kinase II (CK-2) cross-react with CK-2 from other tissues and nuclear form (PK-N2) of the enzyme. Biochem Int 21(4):685–694PubMedGoogle Scholar
  65. 65.
    Kaighn ME, Narayan KS, Ohnuki Y, Lechner JF, Jones LW (1979) Establishment and characterization of a human prostatic carcinoma cell line (PC-3). Invest Urol 17(1):16–23PubMedGoogle Scholar
  66. 66.
    Kozlowski JM, Fidler IJ, Campbell D, Xu Z-l, Kaighn ME, Hart IR (1984) Metastatic behavior of human tumor cell lines grown in the nude mouse. Cancer Res 44(8):3522–3529PubMedGoogle Scholar
  67. 67.
    Hayward SW, Wang Y, Cao M, Hom YK, Zhang B, Grossfeld GD, Sudilovsky D, Cunha GR (2001) Malignant transformation in a nontumorigenic human prostatic epithelial cell line. Cancer Res 61(22):8135–8142PubMedGoogle Scholar
  68. 68.
    Seldin DC, Lou DY, Toselli P, Landesman-Bollag E, Dominguez I (2008) Gene targeting of CK2 catalytic subunits. Mol Cell Biochem 316(1–2):141–147. doi:10.1007/s11010-008-9811-8 PubMedCrossRefGoogle Scholar
  69. 69.
    Geary RS, Yu RZ, Watanabe T, Henry SP, Hardee GE, Chappell A, Matson J, Sasmor H, Cummins L, Levin AA (2003) Pharmacokinetics of a tumor necrosis factor-α phosphorothioate 2’-O-(2-methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 31(11):1419–1428. doi:10.1124/dmd.31.11.1419 PubMedCrossRefGoogle Scholar
  70. 70.
    Furukawa J, Wraight CJ, Freier SM, Peralta E, Atley LM, Monia BP, Gleave ME, Cox ME (2010) Antisense oligonucleotide targeting of insulin-like growth factor-1 receptor (IGF-1R) in prostate cancer. Prostate 70(2):206–218. doi:10.1002/pros.21054 PubMedGoogle Scholar
  71. 71.
    Kunze D, Wuttig D, Kausch I, Blietz C, Blumhoff L, Burmeister Y, Kraemer K, Fuessel S, Toma M, Schwenzer B, Meye A, Grimm MO, Hakenberg OW, Jocham D, Wirth MP (2008) Antisense-mediated inhibition of survivin, hTERT and VEGF in bladder cancer cells in vitro and in vivo. Int J Oncol 32(5):1049–1056PubMedGoogle Scholar
  72. 72.
    Rajasekhar VK, Studer L, Gerald W, Socci ND, Scher HI (2011) Tumour-initiating stem-like cells in human prostate cancer exhibit increased NF-kappaB signalling. Nat Commun 2(1):162. doi:10.1038/ncomms1159 PubMedCrossRefGoogle Scholar
  73. 73.
    Sethi S, Macoska J, Chen W, Sarkar FH (2010) Molecular signature of epithelial-mesenchymal transition (EMT) in human prostate cancer bone metastasis. Am J Transl Res 3(1):90–99PubMedGoogle Scholar
  74. 74.
    Zhang Q, Helfand BT, Jang TL, Zhu LJ, Chen L, Yang XJ, Kozlowski J, Smith N, Kundu SD, Yang G, Raji AA, Javonovic B, Pins M, Lindholm P, Guo Y, Catalona WJ, Lee C (2009) Nuclear factor-κB-mediated transforming growth factor-β-induced expression of vimentin is an independent predictor of biochemical recurrence after radical prostatectomy. Clin Cancer Res 15(10):3557–3567. doi:10.1158/1078-0432.ccr-08-1656 PubMedCrossRefGoogle Scholar
  75. 75.
    Min C, Eddy SF, Sherr DH, Sonenshein GE (2008) NF-κB and epithelial to mesenchymal transition of cancer. J Cell Biochem 104(3):733–744. doi:10.1002/jcb.21695 PubMedCrossRefGoogle Scholar
  76. 76.
    Liu P, Cheng H, Roberts TM, Zhao JJ (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8(8):627–644. doi:10.1038/nrd2926 PubMedCrossRefGoogle Scholar
  77. 77.
    Di Maira G, Salvi M, Arrigoni G, Marin O, Sarno S, Brustolon F, Pinna LA, Ruzzene M (2005) Protein kinase CK2 phosphorylates and upregulates Akt//PKB. Cell Death Differ 12(6):668–677PubMedCrossRefGoogle Scholar
  78. 78.
    Shehata M, Schnabl S, Demirtas D, Hilgarth M, Hubmann R, Ponath E, Badrnya S, Lehner C, Hoelbl A, Duechler M, Gaiger A, Zielinski C, Schwarzmeier JD, Jaeger U (2010) Reconstitution of PTEN activity by CK2 inhibitors and interference with the PI3-K/Akt cascade counteract the antiapoptotic effect of human stromal cells in chronic lymphocytic leukemia. Blood 116(14):2513–2521. doi:10.1182/blood-2009-10-248054 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. (outside the USA) 2011

Authors and Affiliations

  • Janeen H. Trembley
    • 1
    • 2
  • Gretchen M. Unger
    • 6
  • Diane K. Tobolt
    • 6
  • Vicci L. Korman
    • 6
  • Guixia Wang
    • 1
    • 2
    • 8
  • Kashif A. Ahmad
    • 1
    • 2
    • 9
  • Joel W. Slaton
    • 3
  • Betsy T. Kren
    • 1
    • 4
  • Khalil Ahmed
    • 1
    • 2
    • 3
    • 5
    • 7
  1. 1.Research Service, Minneapolis VA Health Care SystemUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of Laboratory Medicine and PathologyUniversity of MinnesotaMinneapolisUSA
  3. 3.Department of UrologyUniversity of MinnesotaMinneapolisUSA
  4. 4.Department of MedicineUniversity of MinnesotaMinneapolisUSA
  5. 5.Masonic Cancer CenterUniversity of MinnesotaMinneapolisUSA
  6. 6.GeneSegues Inc.MinneapolisUSA
  7. 7.Cellular and Molecular Biochemistry Research Laboratory (151)Minneapolis VA Health Care System, University of MinnesotaMinneapolisUSA
  8. 8.The First Hospital of Jilin UniversityJilinChina
  9. 9.Northwestern Health Sciences UniversityBloomingtonUSA

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