Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors

D. Alarcon-Vargas, Z. Zhang, B. Agarwal, K. Challagulla, Sridhar Mani, Ganjam V. Kalpana

Research output: Contribution to journalArticle

54 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)722-734
Number of pages13
JournalOncogene
Volume25
Issue number5
DOIs
StatePublished - Feb 2 2006

Fingerprint

Rhabdoid Tumor
Cyclin D1
Tamoxifen
Apoptosis
Fenretinide
Neoplasms
Drug Combinations
Growth
RNA Interference
Cell Cycle Checkpoints
Heterografts
Pharmacology
Pediatrics
Cell Line
Therapeutics

Keywords

  • 4-HPR
  • Cell cycle and apoptosis
  • Cyclin D1
  • rhabdoid
  • Tamoxifen

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors. / Alarcon-Vargas, D.; Zhang, Z.; Agarwal, B.; Challagulla, K.; Mani, Sridhar; Kalpana, Ganjam V.

In: Oncogene, Vol. 25, No. 5, 02.02.2006, p. 722-734.

Research output: Contribution to journalArticle

Alarcon-Vargas, D, Zhang, Z, Agarwal, B, Challagulla, K, Mani, S & Kalpana, GV 2006, 'Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors', Oncogene, vol. 25, no. 5, pp. 722-734. https://doi.org/10.1038/sj.onc.1209112
Alarcon-Vargas, D. ; Zhang, Z. ; Agarwal, B. ; Challagulla, K. ; Mani, Sridhar ; Kalpana, Ganjam V. / Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors. In: Oncogene. 2006 ; Vol. 25, No. 5. pp. 722-734.
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