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J. Biol. Chem., Vol. 282, Issue 29, 21477-21486, July 20, 2007

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A Transition State Analogue of 5'-Methylthioadenosine Phosphorylase Induces Apoptosis in Head and Neck Cancers^*

Indranil Basu, Grace Cordovano, Ishita Das, Thomas J. Belbin, Chandan Guha^¶1, and Vern L. Schramm²

From the Biochemistry, Pathology, and ^¶Radiation Oncology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461

Methylthio-DADMe-immucillin-A (MT-DADMe-ImmA) is an 86-pM inhibitor of human 5'-methylthioadenosine phosphorylase (MTAP). The sole function of MTAP is to recycle 5'-methylthioadenosine (MTA) to S-adenosylmethionine. Treatment of cultured cells with MT-DADMe-ImmA and MTA inhibited MTAP, increased cellular MTA concentrations, decreased polyamines, and induced apoptosis in FaDu and Cal27, two head and neck squamous cell carcinoma cell lines. The same treatment did not induce apoptosis in normal human fibroblast cell lines (CRL2522 and GM02037) or in MCF7, a breast cancer cell line with an MTAP gene deletion. MT-DADMe-ImmA alone did not induce apoptosis in any cell line, implicating MTA as the active agent. Treatment of sensitive cells caused loss of mitochondrial inner membrane potential, G₂/M arrest, activation of mitochondria-dependent caspases, and apoptosis. Changes in cellular polyamines and MTA levels occurred in both responsive and nonresponsive cells, suggesting cell-specific epigenetic effects. A survey of aberrant DNA methylation in genomic DNA using a microarray of 12,288 CpG island clones revealed decreased CpG island methylation in treated FaDu cells compared with untreated cells. FaDu tumors in a mouse xenograft model were treated with MT-DADMe-ImmA, resulting in tumor remission. The selective action of MT-DADMe-ImmA on head and neck squamous cell carcinoma cells suggests potential as an agent for treatment of cancers sensitive to reduced CpG island methylation.

Received for publication, March 16, 2007 , and in revised form, May 30, 2007.

^* This work was supported by National Institutes of Health Grants GM41916 and CA85953 and a pilot project award from P30 CA013330. 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 Figs. A-C.

¹ To whom correspondence may be addressed: Dept. of Radiation Oncology, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: 718-430-2813; Fax: 718-430-8565; E-mail: cguha{at}montefiore.org.

² To whom correspondence may be addressed: Dept. of Biochemistry, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: 718-430-2813; Fax: 718-430-8565; E-mail: vern{at}aecom.yu.edu.

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