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J. Biol. Chem., Vol. 283, Issue 27, 18678-18684, July 4, 2008

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A Small Molecule Inhibitor of Isoprenylcysteine Carboxymethyltransferase Induces Autophagic Cell Death in PC3 Prostate Cancer Cells^*

Mei Wang, Wanloo Tan, Jin Zhou, Jolene Leow, Meilin Go, How Sung Lee^¶, and Patrick J. Casey¹

From the Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore 169547, the Department of Pharmacy, National University of Singapore, Singapore 117543, and the ^¶Department of Pharmacology, National University of Singapore, Singapore 117597

A number of proteins involved in cell growth control, including members of the Ras family of GTPases, are modified at their C terminus by a three-step posttranslational process termed prenylation. The enzyme isoprenylcysteine carboxylmethyl-transferase (Icmt) catalyzes the last step in this process, and genetic and pharmacological suppression of Icmt activity significantly impacts on cell growth and oncogenesis. Screening of a diverse chemical library led to the identification of a specific small molecule inhibitor of Icmt, cysmethynil, that inhibited growth factor signaling and tumorigenesis in an in vitro cancer cell model (Winter-Vann, A. M., Baron, R. A., Wong, W., dela Cruz, J., York, J. D., Gooden, D. M., Bergo, M. O., Young, S. G., Toone, E. J., and Casey, P. J. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 4336–4341). To further evaluate the mechanisms through which this Icmt inhibitor impacts on cancer cells, we developed both in vitro and in vivo models utilizing PC3 prostate cancer cells. Treatment of these cells with cysmethynil resulted in both an accumulation of cells in the G₁ phase and cell death. Treatment of mice harboring PC3 cell-derived xenograft tumors with cysmethynil resulted in markedly reduced tumor size. Analysis of cell death pathways unexpectedly showed minimal impact of cysmethynil treatment on apoptosis; rather, drug treatment significantly enhanced autophagy and autophagic cell death. Cysmethynil-treated cells displayed reduced mammalian target of rapamycin (mTOR) signaling, providing a potential mechanism for the excessive autophagy as well as G₁ cell cycle arrest observed. These results identify a novel mechanism for the antitumor activity of Icmt inhibition. Further, the dual effects of cell death and cell cycle arrest by cysmethynil treatment strengthen the rationale for targeting Icmt in cancer chemotherapy.

Received for publication, March 7, 2008 , and in revised form, April 21, 2008.

^* This work was supported by the Agency for Science, Technology and Research of Singapore and Singapore Ministry of Health Awards R-913-201-001-304 (to P. J. C.) and Biomedical Research Council Grant 06/1/21/19/487 (to G. M. L. and P. J. C.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text and a supplemental scheme.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed: 2 Jalan Bukit Merah, Singapore, Singapore 169547. Tel.: 65-6516-7251; Fax: 65-6226-3619; E-mail: patrick.casey{at}gms.edu.sg.

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