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J. Biol. Chem., Vol. 282, Issue 39, 28609-28618, September 28, 2007

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EF24 Induces G₂/M Arrest and Apoptosis in Cisplatin-resistant Human Ovarian Cancer Cells by Increasing PTEN Expression^*

Karuppaiyah Selvendiran, Liyue Tong, Shilpa Vishwanath, Anna Bratasz, Nancy J. Trigg, Vijay K. Kutala, Kalman Hideg, and Periannan Kuppusamy¹

From the Department of Internal Medicine, Davis Heart and Lung Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210 and the Institute of Organic and Medicinal Chemistry, University of Pécs, H-7643 Pecs, Hungary

We report that EF24, a synthetic compound 3,5-bis(2-flurobenzylidene)piperidin-4-one, greatly inhibits cisplatin-resistant (CR) human ovarian cancer cell proliferation. The inhibitory effect of EF24 on cell proliferation is associated with G₂/M phase cell cycle arrest and increased G₂/M checkpoint protein (pp53, p53, and p21) levels. Within 24 h following treatment, EF24 induced apoptosis in CR cells. The apoptosis was partially blocked by the general caspase inhibitor z-VAD. Within 12 h, EF24 induced a membranous FasL expression, consistent with a substantial decrease in the Ser⁴⁷³ and Thr³⁰⁸ phosphorylation of Akt, a known negative regulator of FasL transcription. Also, EF24 activated the phosphorylated PTEN and marginally up-regulated total PTEN expression through the inhibition of ubiquitin-mediated PTEN degradation. Suppression of PTEN expression with siRNA significantly reduced the p53 and p21 levels and activated Akt phosphorylation at Ser⁴⁷³ and Thr³⁰⁸, resulting in decreased apoptosis and increased cell survival. On the other hand, overexpression of PTEN markedly induced apoptosis. Our results clearly suggested that EF24 induced significant increase in PTEN expression. The up-regulation of PTEN inhibited Akt and MDM2, which enhanced the level of p53, thereby inducing G₂/M arrest and apoptosis. Therefore, EF24 appears to have a potential therapeutic role in human ovarian cancer through the activation of PTEN.

Received for publication, May 8, 2007 , and in revised form, August 6, 2007.

^* This work was supported by National Institutes of Health Grant CA102264. The synthesis of EF24 was supported by Hungarian Research Fund Grant OTKA T048334. 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.

¹ To whom correspondence should be addressed: The Ohio State University, 420 W. 12th Ave., Columbus, OH 43210. Tel.: 614-292-8998; Fax: 614-292-8454; E-mail: kuppusamy.1{at}osu.edu.

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