Abstract
Rhabdoid tumors (RTs) are aggressive and currently incurable pediatric malignancies. INI1/hSNF5 is a tumor suppressor biallelically inactivated in RTs. Our previous studies have indicated that cyclin D1 is a key downstream target of INI1/hSNF5 and genesis and/or survival of RTs in vivo is critically dependent on the presence of cyclin D1. In this report, we have tested the hypothesis that therapeutic targeting of cyclin D1 is an effective means of treating RTs. We found that RNA interference of cyclin D1 in rhabdoid cells was sufficient to induce G1 arrest and apoptosis. Furthermore, we found that pharmacological intervention with low micromolar concentrations of N-(4-hydroxyphenyl)retinamide (4-HPR), which downmodulates cyclin D1, induced G1 arrest and apoptosis in rhabdoid cell lines. 4-HPR in combination with 4-hydroxy-tamoxifen (4OH-Tam), synergistically inhibited survival as well as anchorage-dependent and -independent growth of rhabdoid cells and caused synergistic induction of cell cycle arrest and apoptosis. 4-HPR and tamoxifen exhibited synergistic growth inhibition of RTs in xenograft models in vivo. The effects of combination of drugs were correlated to the depletion of cyclin D1 levels both in in vitro and in vivo tumor models. These results demonstrate that 4-HPR and tamoxifen are effective chemotherapeutic agents for RTs. We propose that downmodulation of cyclin D1 is a novel and effective therapeutic strategy for RTs.
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References
Ae K, Kobayashi N, Sakuma R, Ogata T, Kuroda H, Kawaguchi N et al. (2002). Oncogene 21: 3112–3120.
Aoyama Y . (2002). Kurume Med J 49: 27–33.
Appierto V, Cavadini E, Pergolizzi R, Cleris L, Lotan R, Canevari S et al. (2001). Br J Cancer 84: 1528–1534.
Argiris A, Wang CX, Whalen SG, DiGiovanna MP . (2004). Clin Cancer Res 10: 1409–1420.
Betz BL, Strobeck MW, Reisman DN, Knudsen ES, Weissman BE . (2002). Oncogene 21: 5193–5203.
Biegel JA, Kalpana G, Knudsen ES, Packer RJ, Roberts CW, Thiele CJ et al. (2002). Cancer Res 62: 323–328.
Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B . (1999). Cancer Res 59: 74–79.
Brockdorff BL, Heiberg I, Lykkesfeldt AE . (2003). Endocr Relat Cancer 10: 579–590.
Chou TC, Riedeout D, Chou J, Bertino JR . (1991). Encyclopedia of Human Biology, vol 2, Dulbecco R (ed). Academic Press: San Diego, pp 371–379.
DiPietrantonio AM, Hsieh TC, Olson SC, Wu JM . (1998). Int J Cancer 78: 53–61.
Dragnev KH, Pitha-Rowe I, Ma Y, Petty WJ, Sekula D, Murphy B et al. (2004). Clin Cancer Res 10: 2570–2577.
Erdreich-Epstein A, Tran LB, Bowman NN, Wang H, Cabot MC, Durden DL et al. (2002). J Biol Chem 277: 49531–49537.
Favoni RE, de Cupis A, Bruno S, Yee D, Ferrera A, Pirani P et al. (1998). Br J Cancer 77: 2138–2147.
Fu M, Wang C, Li Z, Sakamaki T, Pestell RG . (2004). Endocrinology 145: 5439–5447.
Hilden JM, Meerbaum S, Burger P, Finlay J, Janss A, Scheithauer BW et al. (2004). J Clin Oncol 22: 2877–2884.
Jang TJ, Park JH, Cho MY, Kim JR . (2001). Cancer Lett 170: 109–116.
Koshida S, Narita T, Kato H, Yoshida S, Taga T, Ohta S et al. (2002). Jpn J Cancer Res 93: 1351–1357.
Le Marchand L, Seifried A, Lum-Jones A, Donlon T, Wilkens LR . (2003). Jama 290: 2843–2848.
Lee D, Sohn H, Kalpana GV, Choe J . (1999a). Nature 399: 487–491.
Lee TH, Chuang LY, Hung WC . (1999b). Oncogene 18: 4269–4274.
Li WW, Takahashi N, Jhanwar S, Cordon-Cardo C, Elisseyeff Y, Jimeno J et al. (2001). Clin Cancer Res 7: 2908–2911.
Maurer BJ, Melton L, Billups C, Cabot MC, Reynolds CP . (2000). J Natl Cancer Inst 92: 1897–1909.
Mitsiades CS, Poulaki V, Mitsiades N . (2003). J Endocrinol 178: 205–216.
Packer RJ, Biegel JA, Blaney S, Finlay J, Geyer JR, Heideman R et al. (2002). J Pediatr Hematol Oncol 24: 337–342.
Panigone S, Debernardi S, Taya Y, Fontanella E, Airoldi R, Delia D . (2000). Oncogene 19: 4035–4041.
Pirkmaier A, Yuen K, Hendley J, O'Connell MJ, Germain D . (2003). Clin Cancer Res 9: 1877–1884.
Pollack IF, DaRosso RC, Robertson PL, Jakacki RL, Mirro Jr JR, Blatt J et al. (1997). Clin Cancer Res 3: 1109–1115.
Reynolds CP . (2000). Curr Oncol Rep 2: 511–518.
Reynolds CP, Lemons RS . (2001). Hematol Oncol Clin North Am 15: 867–910.
Rousseau C, Pettersson F, Couture MC, Paquin A, Galipeau J, Mader Jr S et al. (2003). J Steroid Biochem Mol Biol 86: 1–14.
Simeone AM, Ekmekcioglu S, Broemeling LD, Grimm EA, Tari AM . (2002). Mol Cancer Ther 1: 1009–1017.
Singletary SE, Atkinson EN, Hoque A, Sneige N, Sahin AA, Fritsche Jr HA et al. (2002). Clin Cancer Res 8: 2835–2842.
Tsikitis M, Zhang Z, Edelman W, Zagzag D, Kalpana GV . (2005). Proc Natl Acad Sci USA 102: 12129–12134.
Versteege I, Medjkane S, Rouillard D, Delattre O . (2002). Oncogene 21: 6403–6412.
Versteege I, Sevenet N, Lange J, Rousseau-Merck MF, Ambros P, Handgretinger R et al. (1998). Nature 394: 203–206.
Vries RG, Bezrookove V, Zuijderduijn LM, Kia SK, Houweling A, Oruetxebarria I et al. (2005). Genes Dev 19: 665–670.
Wang H, Charles AG, Frankel AJ, Cabot MC . (2003). Urology 61: 1047–1052.
Wu K, Wang C, D'Amico M, Lee RJ, Albanese C, Pestell RG et al. (2002). Mol Cancer Ther 1: 695–706.
Zeisig R, Teppke AD, Behrens D, Fichtner I . (2004). Breast Cancer Res Treat 87: 245–254.
Zhang ZK, Davies KP, Allen J, Zhu L, Pestell RG, Zagzag D et al. (2002). Mol Cell Biol 22: 5975–5988.
Acknowledgements
We thank Drs Prasad, Goldman and Birshtein at the Albert Einstein College of Medicine for critically reading the manuscript and for useful discussions. We thank Dr Beigel, University of Pennsylvania, for the kind gift of some rhabdoid cell lines and Dr Tsikitis for initial technical assistance with xenograft mice. We thank Drs M Smith and J Zweibel for kindly providing 4-HPR for animal studies. This work was supported by grants from The American Cancer Society (RSG CCG-10493) to GVK, Albert Einstein Cancer Center Pilot Project Award (CCSG # P30 CA13330) to GVK and SM, The Damon Runyon Clinical Investigator Award (CI02-12) to SM. GVK is a recipient of Irma T Hirschl Career Scientist Award and is a Mark Trauner Faculty Scholar in NeuroOncology.
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Alarcon-Vargas, D., Zhang, Z., Agarwal, B. et al. Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors. Oncogene 25, 722–734 (2006). https://doi.org/10.1038/sj.onc.1209112
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DOI: https://doi.org/10.1038/sj.onc.1209112
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