Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity

Rodger E. Tiedemann, Xinliang Mao, Chang Xin Shi, Xiao Zhu Yuan, Stephen E. Palmer, Michael Sebag, Ron Marler, Marta Chesi, Rafael Fonseca, P. Leif Bergsagel, Aaron D. Schimmer, A. Keith Stewart

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Knockout and transgenic studies in mice demonstrate that normal somatic tissues redundantly express 3 cyclin D proteins, whereas tumor cells seem dependent on a single overexpressed cyclin D. Thus, selective suppression of the individual cyclin D deregulated in a tumor represents a biologically valid approach to targeted cancer therapy. In multiple myeloma, overexpression of 1 of the cyclin D proteins is a ubiquitous feature, unifying at least 7 different initiating genetic events. We demonstrate here that RNAi of genes encoding cyclin D1 and cyclin D2 (CCND1 and CCND2, respectively) inhibits proliferation and is progressively cytotoxic in human myeloma cells. By screening a chemical library using a cell-based assay for inhibition of CCND2 trans-activation, we identified the plant cytokinin kinetin riboside as an inhibitor of CCND2 trans-activation. Kinetin riboside induced marked suppression of CCND2 transcription and rapidly suppressed cyclin D1 and D2 protein expression in primary myeloma cells and tumor lines, causing cell-cycle arrest, tumor cell-selective apoptosis, and inhibition of myeloma growth in xenografted mice. Mechanistically, kinetin riboside upregulated expression of transcription repressor isoforms of cAMP-response element modulator (CREM) and blocked both trans-activation of CCND2 by various myeloma oncogenes and cis-activation of translocated CCND1, suggesting induction of an overriding repressor activity that blocks multiple oncogenic pathways targeting cyclin D genes. These data support targeted repression of cyclin D genes as a therapeutic strategy for human malignancies.

Original languageEnglish (US)
Pages (from-to)1750-1764
Number of pages15
JournalJournal of Clinical Investigation
Volume118
Issue number5
DOIs
StatePublished - May 1 2008

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity'. Together they form a unique fingerprint.

  • Cite this