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Anti-neoplastic effect of protein kinase CK2 inhibitor, 2-dimethylamino-4,5,6,7-tetrabromobenzimidazole (DMAT), on growth and hormonal activity of human adrenocortical carcinoma cell line (H295R) in vitro

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Abstract

Several studies indicate the involvement of protein kinases in the progression of various malignancies. Kinase inhibitors are therefore becoming important anticancer drugs. CK2 kinase (casein kinase-2) has been suggested to be a constituent of a neoplastic milleu, and its inhibition might represent a new approach to cancer therapy. Adrenocortical carcinomas (ACCs) are highly malignant neoplasms with poor overall prognosis. We have examined the effects of 2-dimethylamino-4,5,6,7-tetrabromobenzimidazole (DMAT), a potent CK2 inhibitor, on the H295R human adrenocortical cancer cell line. Treatment with DMAT decreases the secretion of aldosterone, dehydroepiandrosterone sulfate, and androstendione and results in an accumulation of 17-OH-progesterone. Cell growth as measured by the MTT and 5-bromo-2′-deoxyuridine incorporation assays is inhibited, and cell cycle analysis has revealed a slight induction of apoptosis. Thus, CK2 kinase activity is probably involved in human ACC endocrine activity and growth.

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References

  • Abiven G, Coste J, Groussin L, Anract P, Tissier F, Legmann P, Dousset B, Bertagna X, Bertherat J (2006) Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metab 91:2650–2655

    Article  CAS  PubMed  Google Scholar 

  • Ahlman H, Khorram-Manesh A, Jansson S, Wängberg B, Nilsson O, Jacobsson CE, Lindstedt S (2001) Cytotoxic treatment of adrenocortical carcinoma. World J Surg 25:927–933

    Article  CAS  PubMed  Google Scholar 

  • Ahmad KA, Wang G, Slaton J, Unger G, Ahmed K (2005) Targeting CK2 for cancer therapy. Anticancer Drugs 16:1037–1043

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Ahmed K, Gerber DA, Cochet C (2002) Joining the cell survival squad: an emerging role for protein kinase CK2. Trends Cell Biol 12:226–230

    Article  CAS  PubMed  Google Scholar 

  • Butler C, Butler WM, Rizvi AA (2009) Sustained remission with the kinase inhibitor sorafenib in Stage IV metastatic adrenocortical carcinoma. Endocr Pract 26:1–19

    Google Scholar 

  • Berruti A, Terzolo M, Sperone P, Pia A, Casa SD, Gross DJ, Carnaghi C, Casali P, Porpiglia F, Mantero F, Reimondo G, Angeli A, Dogliotti L (2005) Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer 12:657–666

    Article  CAS  PubMed  Google Scholar 

  • Cozza G, Bortolato A, Moro S (2009) How druggable is protein kinase CK2? Med Res Rev (in press) doi:10.1002/med.20164)

  • Crucitti F, Bellantone R, Ferrante A, Boscherini M, Crucitti P (1996) The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group. Surgery 119:161–170

    Article  CAS  PubMed  Google Scholar 

  • Di Maira G, Brustolon F, Bertacchini J, Tosoni K, Marmiroli S, Pinna LA, Ruzzene M (2007) Pharmacological inhibition of protein kinase CK2 reverts the multidrug resistance phenotype of a CEM cell line characterized by high CK2 level. Oncogene 26:6915–6926

    Article  PubMed  Google Scholar 

  • Di Maira G, Brustolon F, Tosoni K, Belli S, Krämer SD, Pinna LA, Ruzzene M (2008) Comparative analysis of CK2 expression and function in tumor cell lines displaying sensitivity vs. resistance to chemical induced apoptosis. Mol Cell Biochem 316:155–161

    Article  PubMed  Google Scholar 

  • Duncan JS, Litchfield DW (2008) Too much of a good thing: the role of protein kinase CK2 in tumorigenesis and prospects for therapeutic inhibition of CK2. Biochim Biophys Acta 1784:33–47

    CAS  PubMed  Google Scholar 

  • Fassnacht M, Allolio B (2009) Clinical management of adrenocortical carcinoma. Best Pract Res Clin Endocrinol Metab 23:273–289

    Article  CAS  PubMed  Google Scholar 

  • Fassnacht M, Kreissl MC, Weismann D, Allolio B (2009) New targets and therapeutic approaches for endocrine malignancies. Pharmacol Ther 123:117–141

    Article  CAS  PubMed  Google Scholar 

  • Faust M, Montenarh M (2000) Subcellular localization of protein kinase CK2. A key to its function? Cell Tissue Res 301:329–340

    Article  CAS  PubMed  Google Scholar 

  • Flynn SD, Murren JR, Kirby WM, Honig J, Kan L, Kinder BK (1992) P-glycoprotein expression and multidrug resistance in adrenocortical carcinoma. Surgery 112:981–986

    CAS  PubMed  Google Scholar 

  • Gaujoux S, Tissier F, Groussin L, Libé R, Ragazzon B, Launay P, Audebourg A, Dousset B, Bertagna X, Bertherat J (2008) Wnt/beta-catenin and 3′,5′-cyclic adenosine 5′-monophosphate/protein kinase A signaling pathways alterations and somatic beta-catenin gene mutations in the progression of adrenocortical tumors. J Clin Endocrinol Metab 93:4135–4140

    Article  CAS  PubMed  Google Scholar 

  • Gerlier D, Thomasset N (1986) Use of MTT colorimetric assay to measure cell activation. J Immunol Methods 94:57–63

    Article  CAS  PubMed  Google Scholar 

  • Gietz RD, Graham KC, Litchfield DW (1995) Interactions between the subunits of casein kinase II. J Biol Chem 270:13017–13021

    Article  CAS  PubMed  Google Scholar 

  • Graham KC, Litchfield DW (2000) The regulatory beta subunit of protein kinase CK2 mediates formation of tetrameric CK2 complexes. J Biol Chem 275:5003–5010

    Article  CAS  PubMed  Google Scholar 

  • Guerra B, Issinger OG (1999) Protein kinase CK2 and its role in cellular proliferation, development and pathology. Electrophoresis 20:391–408

    Article  CAS  PubMed  Google Scholar 

  • 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 276:5992–5999

    Article  CAS  PubMed  Google Scholar 

  • Heil J, Reifferscheid G (1992) Detection of mammalian carcinogens with an immunological DNA synthesis-inhibition test. Carcinogenesis 13:2389–2394

    Article  CAS  PubMed  Google Scholar 

  • Izeradjene K, Douglas L, Delaney A, Houghton JA (2005) Casein kinase II (CK2) enhances death-inducing signaling complex (DISC) activity in TRAIL-induced apoptosis in human colon carcinoma cell lines. Oncogene 24:2050–2058

    Article  CAS  PubMed  Google Scholar 

  • Khan TS, Imam H, Juhlin C, Skogseid B, Grondal S, Tibblin S, Wilander E, Oberg K, Eriksson B (2000) Streptozocin and o, p’DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use. Ann Oncol 11:1281–1287

    Article  CAS  PubMed  Google Scholar 

  • Kim JS, Eom JI, Cheong JW, Choi AJ, Lee JK, Yang WI, Min YH (2007) Protein kinase CK2alpha as an unfavorable prognostic marker and novel therapeutic target in acute myeloid leukemia. Clin Cancer Res 13:1019–1028

    Article  CAS  PubMed  Google Scholar 

  • Kirschner LS (2006) Emerging treatment strategies for adrenocortical carcinoma: a new hope. J Clin Endocrinol Metab 91:14–21

    Article  CAS  PubMed  Google Scholar 

  • 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 43:928–934

    Article  CAS  PubMed  Google Scholar 

  • Lawnicka H, Kowalewicz-Kulbat M, Sicinska P, Altmann KH, Hofmann T, Stepien H (2009) Resorcylic acid lactone L-783, 277 inhibits the growth of the human adrenal cancer cell line H295R in vitro. Int J Immunopathol Pharmacol 22:889–895

    CAS  PubMed  Google Scholar 

  • Lee JO, Lee KW, Kim CJ, Kim YJ, Lee HE, Kim H, Kim JH, Bang SM, Kim JS, Lee JS (2009) Metastatic adrenocortical carcinoma treated with sunitinib: a case report. Jpn J Clin Oncol 39:183–185

    Article  PubMed  Google Scholar 

  • Libe R, Fratticci A, Bertherat J (2007) Adrenocortical cancer: pathophysiology and clinical management. Endocr Relat Cancer 14:13–28

    Article  CAS  PubMed  Google Scholar 

  • Mishra S, Pertz V, Zhang B, Kaur P, Shimada H, Groffen J, Kazimierczuk Z, Pinna LA, Heisterkamp N (2007) Treatment of P190 Bcr/Abl lymphoblastic leukemia cells with inhibitors of the serine/threonine kinase CK2. Leukemia 21:178–180

    Article  CAS  PubMed  Google Scholar 

  • 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 10:5792–5803

    Article  CAS  PubMed  Google Scholar 

  • Pagano MA, Meggio F, Ruzzene M, Andrzejewska M, Kazimierczuk Z, Pinna LA (2004) 2-Dimethylamino-4, 5, 6, 7-tetrabromo-1H-benzimidazole: a novel powerful and selective inhibitor of protein kinase CK2. Biochem Biophys Res Commun 321:1040–1044

    Article  CAS  PubMed  Google Scholar 

  • Patalano A, Brancato V, Mantero F (2009) Adrenocortical cancer treatment. Horm Res 71 (Suppl 1):99–104

    Article  CAS  PubMed  Google Scholar 

  • Ruzzene M, Pinna LA (2010) Addiction to protein kinase CK2: a common denominator of diverse cancer cells? Biochim Biophys Acta 1804:499-504

    CAS  PubMed  Google Scholar 

  • Seldin DC, Landesman-Bollag E, Farago M, Currier N, Lou D, Dominguez I (2005) CK2 as a positive regulator of Wnt signalling and tumourigenesis. Mol Cell Biochem 274:63–67

    Article  CAS  PubMed  Google Scholar 

  • Shin S, Lee Y, Kim W, Ko H, Choi H, Kim K (2005) Caspase-2 primes cancer cells for TRAIL-mediated apoptosis by processing procaspase-8. EMBO J 24:3532–3542

    Article  CAS  PubMed  Google Scholar 

  • Soon PS, McDonald KL, Robinson BG, Sidhu SB (2008) Molecular markers and the pathogenesis of adrenocortical cancer. Oncologist 13:548–561

    Article  CAS  PubMed  Google Scholar 

  • Tadjine M, Lampron A, Ouadi L, Bourdeau I (2008) Frequent mutations of beta-catenin gene in sporadic secreting adrenocortical adenomas. Clin Endocrinol (Oxf) 68:264–270

    CAS  Google Scholar 

  • Tawfic S, Yu S, Wang H, Faust R, Davis A, Ahmed K (2001) Protein kinase CK2 signal in neoplasia. Histol Histopathol 16:573–582

    CAS  PubMed  Google Scholar 

  • Tissier F, Cavard C, Groussin L, Perlemoine K, Fumey G, Hagneré AM, René-Corail F, Jullian E, Gicquel C, Bertagna X, Vacher-Lavenu MC, Perret C, Bertherat J (2005) Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res 65:7622–7627

    CAS  PubMed  Google Scholar 

  • Wang G, Unger G, Ahmad KA, Slaton JW, Ahmed K (2005) Downregulation of CK2 induces apoptosis in cancer cells—a potential approach to cancer therapy. Mol Cell Biochem 274:77–84

    Article  CAS  PubMed  Google Scholar 

  • Wang G, Ahmad KA, Ahmed K (2006) Role of protein kinase CK2 in the regulation of tumor necrosis factor-related apoptosis inducing ligand-induced apoptosis in prostate cancer cells. Cancer Res 66:2242–2249

    Article  CAS  PubMed  Google Scholar 

  • Yamane K, Kinsella TJ (2005) Casein kinase 2 regulates both apoptosis and the cell cycle following DNA damage induced by 6-thioguanine. Clin Cancer Res 11:2355–2363

    Article  CAS  PubMed  Google Scholar 

  • Yde CW, Frogne T, Lykkesfeldt AE, Fichtner I, Issinger OG, Stenvang J (2007) Induction of cell death in antiestrogen resistant human breast cancer cells by the protein kinase CK2 inhibitor DMAT. Cancer Lett 256:229–237

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Immunoendocrinology, 1st Chair of Endocrinology, Medical University of Lodz, Dr. Sterling 3 Street, 91-425, Lodz, Poland

    Hanna Lawnicka & Henryk Stepien

  2. Department of Immunology and Infectious Biology, University of Lodz, Banacha 12/16, 90-237, Lodz, Poland

    Magdalena Kowalewicz-Kulbat

  3. Department of Molecular Biophysics, University of Lodz, Banacha 12/16, 90-237, Lodz, Poland

    Paulina Sicinska

  4. Department of Experimental Pharmacology, Mossakowski Medical Research Center, Polish Academy of Sciences, Pawinskiego 5, 02-124, Warsaw, Poland

    Zygmunt Kazimierczuk & Pawel Grieb

Authors
  1. Hanna Lawnicka
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  2. Magdalena Kowalewicz-Kulbat
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  3. Paulina Sicinska
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  4. Zygmunt Kazimierczuk
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  5. Pawel Grieb
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  6. Henryk Stepien
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Corresponding author

Correspondence to Henryk Stepien.

Additional information

This work was supported by European Cooperation in the field of Scientific and Technical Research (COST ACTION, grant no. CM0602) and the Polish Ministry of Science and Higher Education (grant no. 505-04-001). The synthesis of DMAT was supported by the Foundation for the Development of Diagnostics and Therapy, Warsaw, Poland.

Conflict of interest statement

All the above authors state that they have no financial or personal relationships with other people or organizations that could inappropriately influence (bias) this work.

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Lawnicka, H., Kowalewicz-Kulbat, M., Sicinska, P. et al. Anti-neoplastic effect of protein kinase CK2 inhibitor, 2-dimethylamino-4,5,6,7-tetrabromobenzimidazole (DMAT), on growth and hormonal activity of human adrenocortical carcinoma cell line (H295R) in vitro. Cell Tissue Res 340, 371–379 (2010). https://doi.org/10.1007/s00441-010-0960-1

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