Repression of cyclin D1 as a target for germ cell tumors

Sarah J. Freemantle, Angelina V. Vaseva, Katherine E. Ewings, Thomas Bee, Katey A. Krizan, Mark R. Kelley, Eyas M. Hattab, Vincent A. Memoli, Candice C. Black, Michael J. Spinella, Ethan Dmitrovsky

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Metastatic germ cell tumors (GCT) are curable, however GCTs refractory to cisplatin-based chemotherapy have a poor prognosis. This study explores D-type cyclins as molecular targets in GCTs because all-trans-retinoic acid (RA)-mediated differentiation of the human embryonal carcinoma (EC) cell line NT2/D1 is associated with G1 cell cycle arrest and proteasomal degradation of cyclin D1. RA effects on D-type cyclins are compared in human EC cells that are RA sensitive or dually RA and cisplatin resistant (NT2/D1-R1) and in clinical GCTs that have both EC and mature teratoma components. Notably, GCT differentiation was associated with reduced cyclin D1 but increased cyclin D3 expression. RA was shown here to repress cyclin D1 through a transcriptional mechanism in addition to causing its degradation. The siRNA-mediated repression of individual cyclin D species resulted in growth inhibition in both RA sensitive and resistant EC cells. Only repression of cyclin D1 occurred in vitro and when clinical GCTs mature, implicating cyclin D1 as a molecular therapeutic target. To confirm this, the EGFR-tyrosine kinase inhibitor, Erlotinib, was used to repress cyclin D1. This inhibited proliferation in RA and cisplatin sensitive and resistant EC cells. Taken together, these findings implicate cyclin D1 targeting agents for the treatment of GCTs.

Original languageEnglish (US)
Pages (from-to)333-340
Number of pages8
JournalInternational journal of oncology
Volume30
Issue number2
StatePublished - Feb 2007

Keywords

  • Cyclin D1
  • Cyclin D3
  • Germ cell tumor differentiation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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  • Cite this

    Freemantle, S. J., Vaseva, A. V., Ewings, K. E., Bee, T., Krizan, K. A., Kelley, M. R., Hattab, E. M., Memoli, V. A., Black, C. C., Spinella, M. J., & Dmitrovsky, E. (2007). Repression of cyclin D1 as a target for germ cell tumors. International journal of oncology, 30(2), 333-340.