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A critical role for choline kinase-α in the aggressiveness of bladder carcinomas

Abstract

Bladder cancer is one of the most common causes of death in industrialized countries. New tumor markers and therapeutic approaches are still needed to improve the management of bladder cancer patients. Choline kinase-α (ChoKα) is a metabolic enzyme that has a role in cell proliferation and transformation. Inhibitors of ChoKα show antitumoral activity and are expected to be introduced soon in clinical trials. This study aims to assess whether ChoKα plays a role in the aggressiveness of bladder tumors and constitutes a new approach for bladder cancer treatment. We show here that ChoKα is constitutively altered in human bladder tumor cells. Furthermore, in vivo murine models, including an orthotopic model to mimic as much as possible the physiological conditions, revealed that increased levels of ChoKα potentiate both tumor formation (P0.0001) and aggressiveness of the disease on different end points (P=0.011). Accordingly, increased levels of ChoKα significantly reduce survival of mice with bladder cancer (P=0.05). Finally, treatment with a ChoKα-specific inhibitor resulted in a significant inhibition of tumor growth (P=0.02) and in a relevant increase in survival (P=0.03).

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References

  • Al-Saffar NM, Troy H, Ramirez de Molina A, Jackson LE, Madhu B, Griffiths JR et al. (2006). Noninvasive magnetic resonance spectroscopic pharmacodynamic markers of the choline kinase inhibitor MN58b in human carcinoma models. Cancer Res 66: 427–434.

    Article  CAS  Google Scholar 

  • Aoyama C, Liao H, Ishidate K . (2004). Structure and function of choline kinase isoforms in mammalian cells. Prog Lipid Res 43: 266–281.

    Article  CAS  Google Scholar 

  • Banez-Coronel M, Ramirez de Molina A, Rodríguez-González A, Sarmentero J, Ramos MA, García-Cabezas MA et al. (2008). Choline kinase alpha depletion selectively kills tumoral cells. Curr Cancer Drug Targets 8: 709–719.

    Article  CAS  Google Scholar 

  • Cordon-Cardo C, Zhang ZF, Dalbagni G, Drobnjak M, Charytonowicz E, Hu SX et al. (1997). Cooperative effects of p53 and pRB alterations in primary superficial bladder tumors. Cancer Res 57: 1217–1221.

    CAS  Google Scholar 

  • Chin J, Kadhim S, Garcia B, Kim YS, Karlik S . (1991). Magnetic resonance imaging for detecting and treatment monitoring of orthotopic murine bladder tumor implants. J Urol 145: 1297–1301.

    Article  CAS  Google Scholar 

  • Gallego-Ortega D, Ramirez De Molina A, Gutierrez R, Ramos MA, Sarmentero J, Cejas P et al. (2006). Generation and characterization of monoclonal antibodies against choline kinase alpha and their potential use as diagnostic tools in cancer. Int J Oncol 29: 335–340.

    CAS  PubMed  Google Scholar 

  • Gallego-Ortega D, Ramirez de Molina A, Ramos MA, Valdes-Mora F, Barderas MG, Sarmentero-Estrada J et al. (2009). Differential role of human choline kinase alpha and beta enzymes in lipid metabolism: potential implications in cancer onset and treatment (submitted).

  • Garraway LA, Sellers WR . (2006). Lineage dependency and lineage-survival oncogenes in human cancer. Nat Rev Cancer 6: 593–602.

    Article  CAS  Google Scholar 

  • Glunde K, Bhujwalla ZM . (2007). Choline kinase alpha in cancer prognosis and treatment. Lancet Oncol 8: 855–857.

    Article  CAS  Google Scholar 

  • Glunde K, Raman V, Mori N, Bhujwalla ZM . (2005). RNA interference-mediated choline kinase suppression in breast cancer cells induces differentiation and reduces proliferation. Cancer Res 65: 11034–11043.

    Article  CAS  Google Scholar 

  • Hernandez-Alcoceba R, Fernandez F, Lacal JC . (1999). In vivo antitumor activity of choline kinase inhibitors: a novel target for anticancer drug discovery. Cancer Res 59: 3112–3118.

    CAS  PubMed  Google Scholar 

  • Hernandez-Alcoceba R, Saniger L, Campos J, Nunez MC, Khaless F, Gallo MA et al. (1997). Choline kinase inhibitors as a novel approach for antiproliferative drug design. Oncogene 15: 2289–2301.

    Article  CAS  Google Scholar 

  • Hernando E, Orlow I, Liberal V, Nohales G, Benezra R, Cordon-Cardo C . (2001). Molecular analyses of the mitotic checkpoint components hsMAD2, hBUB1 and hBUB3 in human cancer. Int J Cancer 95: 223–227.

    Article  CAS  Google Scholar 

  • Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ . (2007). Cancer statistics, 2007. CA Cancer J Clin 57: 43–66.

    Article  Google Scholar 

  • Jonkers J, Berns A . (2004). Oncogene addiction: sometimes a temporary slavery. Cancer Cell 6: 535–538.

    CAS  Google Scholar 

  • Kikuchi E, Menendez S, Ohori M, Cordon-Cardo C, Kasahara N, Bochner BH . (2004). Inhibition of orthotopic human bladder tumor growth by lentiviral gene transfer of endostatin. Clin Cancer Res 10: 1835–1842.

    Article  CAS  Google Scholar 

  • Kikuchi E, Xu S, Ohori M, Matei C, Lupu M, Menendez S et al. (2003). Detection and quantitative analysis of early stage orthotopic murine bladder tumor using in vivo magnetic resonance imaging. J Urol 170: 1375–1378.

    Article  Google Scholar 

  • Lacal JC . (2001). Choline kinase: a novel target for antitumor drugs. IDrugs 4: 419–426.

    CAS  PubMed  Google Scholar 

  • Lu ML, Wikman F, Orntoft TF, Charytonowicz E, Rabbani F, Zhang Z et al. (2002). Impact of alterations affecting the p53 pathway in bladder cancer on clinical outcome, assessed by conventional and array-based methods. Clin Cancer Res 8: 171–179.

    CAS  PubMed  Google Scholar 

  • Mullerad M, Bochner BH, Adusumilli PS, Bhargava A, Kikuchi E, Hui-Ni C et al. (2005). Herpes simplex virus based gene therapy enhances the efficacy of mitomycin C for the treatment of human bladder transitional cell carcinoma. J Urol 174: 741–746.

    Article  CAS  Google Scholar 

  • Nakagami K, Uchida T, Ohwada S, Koibuchi Y, Suda Y, Sekine T et al. (1999). Increased choline kinase activity and elevated phosphocholine levels in human colon cancer. Jpn J Cancer Res 90: 419–424.

    Article  CAS  Google Scholar 

  • Oliveira PA, Colaco A, De la Cruz PL, Lopes C . (2006). Experimental bladder carcinogenesis-rodent models. Exp Oncol 28: 2–11.

    CAS  PubMed  Google Scholar 

  • Quek ML, Stein JP, Nichols PW, Cai J, Miranda G, Groshen S et al. (2005). Prognostic significance of lymphovascular invasion of bladder cancer treated with radical cystectomy. J Urol 174: 103–106.

    Article  Google Scholar 

  • Ramirez de Molina A, Banez-Coronel M, Gutierrez R, Rodriguez-Gonzalez A, Olmeda D, Megias D et al. (2004). Choline kinase activation is a critical requirement for the proliferation of primary human mammary epithelial cells and breast tumor progression. Cancer Res 64: 6732–6739.

    Article  Google Scholar 

  • Ramirez de Molina A, Gallego-Ortega D, Sarmentero J, Banez-Coronel M, Martin-Cantalejo Y, Lacal JC . (2005). Choline kinase is a novel oncogene that potentiates RhoA-induced carcinogenesis. Cancer Res 65: 5647–5653.

    Article  CAS  Google Scholar 

  • Ramirez de Molina A, Penalva V, Lucas L, Lacal JC . (2002a). Regulation of choline kinase activity by Ras proteins involves Ral-GDS and PI3 K. Oncogene 21: 937–946.

    Article  CAS  Google Scholar 

  • Ramirez de Molina A, Rodriguez-Gonzalez A, Gutierrez R, Martinez-Pineiro L, Sanchez J, Bonilla F et al. (2002b). Overexpression of choline kinase is a frequent feature in human tumor-derived cell lines and in lung, prostate, and colorectal human cancers. Biochem Biophys Res Commun 296: 580–583.

    Article  CAS  Google Scholar 

  • Ramirez de Molina A, Sarmentero-Estrada J, Belda-Iniesta C, Taron M, Ramirez de Molina V, Cejas P et al. (2007). Expression of choline kinase alpha to predict outcome in patients with early-stage non-small-cell lung cancer: a retrospective study. Lancet Oncol 8: 889–897.

    Article  CAS  Google Scholar 

  • Rodriguez-Gonzalez A, Ramirez de Molina A, Banez-Coronel M, Megias D, Lacal JC . (2005). Inhibition of choline kinase renders a highly selective cytotoxic effect in tumour cells through a mitochondrial independent mechanism. Int J Oncol 26: 999–1008.

    CAS  PubMed  Google Scholar 

  • Rodriguez-Gonzalez A, Ramirez de Molina A, Fernandez F, Lacal JC . (2004). Choline kinase inhibition induces the increase in ceramides resulting in a highly specific and selective cytotoxic antitumoral strategy as a potential mechanism of action. Oncogene 23: 8247–8259.

    Article  CAS  Google Scholar 

  • Rodriguez-Gonzalez A, Ramirez de Molina A, Fernandez F, Ramos MA, del Carmen Nunez M, Campos J et al. (2003). Inhibition of choline kinase as a specific cytotoxic strategy in oncogene-transformed cells. Oncogene 22: 8803–8812.

    Article  CAS  Google Scholar 

  • Sanderson KM, Cai J, Miranda G, Skinner DG, Stein JP . (2007). Upper tract urothelial recurrence following radical cystectomy for transitional cell carcinoma of the bladder: an analysis of 1,069 patients with 10-year followup. J Urol 177: 2088–2094.

    Article  Google Scholar 

  • Weinstein IB, Joe AK . (2006). Mechanisms of disease: oncogene addiction--a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 3: 448–457.

    Article  CAS  Google Scholar 

  • Wu XR . (2005). Urothelial tumorigenesis: a tale of divergent pathways. Nat Rev Cancer 5: 713–725.

    Article  CAS  Google Scholar 

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Acknowledgements

We gratefully thank E Charytonowicz for technical assistance during the intravesical instillations; Mihaela Lupu and Cornelia Mateia for MRI monitoring; Miguel Angel García-Cabezas for helping with the histopathological analysis. This work has been supported by a grant to ARM from Fundación Mutua Madrileña (2006), and grants to JCL from Comunidad de Madrid (S-BIO/0280/2006), Ministerio de Educación y Ciencia (SAF2004-0577 and SAF2005-06195-C02-01), EU grant (LSHG-CT-2006-037278), Ministerio de Sanidad (RD06/0020/ 0016), Fundación Mutua Madrileña (2006), Acción transversal del Cáncer (FIS, Instituto de Salud Carlos III) and NIH 1R24CA83084, NIH 1R24CA83084. TCD Pharma (Madrid, Spain) provided ChoKα monoclonal antibody and MN58b free of charge.

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Correspondence to A Ramírez de Molina.

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Hernando, E., Sarmentero-Estrada, J., Koppie, T. et al. A critical role for choline kinase-α in the aggressiveness of bladder carcinomas. Oncogene 28, 2425–2435 (2009). https://doi.org/10.1038/onc.2009.91

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