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Research Articles: Therapeutics, Targets, and Development

Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function

¹ Winship Cancer Institute, ² Department of Chemistry, Emory University, Atlanta, Georgia; ³ Weill Medical College, Cornell University, New York, New York; and ⁴ M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Adam I. Marcus, Winship Cancer Institute, Emory University, Atlanta, GA 30322. Phone: 404-778-4597. E-mail: adam.marcus{at}emory.org

Abstract

Farnesyl transferase inhibitors (FTI) exhibit anticancer activity as a single agent in preclinical studies and show promise in combination with other therapeutics in clinical trials. Previous studies show that FTIs arrest cancer cells in mitosis; however, the mechanism by which this occurs is unclear. Here, we observed that treatment of various cancer cell lines with the FTI lonafarnib caused mitotic chromosomal alignment defects, leaving cells in a pseudometaphase state, whereby both aligned chromosomes and chromosomes juxtaposed to the spindle poles (termed "lagging chromosomes") were observed in the same cell. To determine how this occurs, we investigated the functionality of two farnesylated mitotic proteins, CENP-E and CENP-F, which mediate chromosomal capture and alignment. The data show that lonafarnib in proliferating cancer cells depletes CENP-E and CENP-F from metaphase but not prometaphase kinetochores. Loss of CENP-E and CENP-F metaphase localization triggered aberrant chromosomal maintenance, causing aligned chromosomes to be prematurely released from the spindle equator and become lagging chromosomes, resulting in a mitotic delay. Furthermore, lonafarnib treatment reduces sister kinetochore tension and activates the BubR1 spindle checkpoint, suggesting that farnesylation of CENP-E and CENP-F is critical for their functionality in maintaining kinetochore-microtubule interactions. Importantly, apparently similar chromosomal alignment defects were observed in head and neck tumors samples from a phase I trial with lonafarnib, providing support that lonafarnib disrupts chromosomal maintenance in human cancers. Lastly, to examine how farnesylation could regulate CENP-E in mediating kinetochore-microtubule attachments, we examined possible docking motifs of a farnesyl group on the outer surface of the microtubule. This analysis revealed three hydrophobic patches on the tubulin dimer for insertion of a farnesyl group, alluding to the possibility of an association between a farnesyl group and the microtubule. [Mol Cancer Ther 2007;6(4):1317–28]

Grant support: NIH/National Cancer Institute Lung Cancer Program Project grant 1PO1 CA116676 (F.R. Khuri, P. Giannakakou, and A.I.Marcus) and NIH grant CA-69571 (J.P. Snyder).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: K. Schafer-Hales and J. Iaconelli contributed equally to this work.

⁵ Supplementary material for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournal.org).

Received 11/14/06; revised 2/ 7/07; accepted 2/22/07.

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