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J. Biol. Chem., Vol. 280, Issue 31, 28519-28528, August 5, 2005

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Checkpoint Kinase 1 Regulates Diallyl Trisulfide-induced Mitotic Arrest in Human Prostate Cancer Cells^*

Anna Herman-Antosiewicz and Shivendra V. Singh

From the Department of Pharmacology and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213

We have shown previously that diallyl trisulfide (DATS), a constituent of processed garlic, inhibits proliferation of PC-3 and DU145 human prostate cancer cells by causing G₂-M phase cell cycle arrest in association with inhibition of cyclin-dependent kinase 1 activity and hyperphosphorylation of Cdc25C at Ser²¹⁶. Here, we report that DATS-treated PC-3 and DU145 cells are also arrested in mitosis as judged by microscopy following staining with anti--tubulin antibody and 4',6-diamidino-2-phenylindole and flow cytometric analysis of Ser¹⁰ phosphorylation of histone H3. The DATS treatment caused activation of checkpoint kinase 1 and checkpoint kinase 2, which are intermediaries of DNA damage checkpoints and implicated in Ser²¹⁶ phosphorylation of Cdc25C. The diallyl trisulfide-induced Ser²¹⁶ phosphorylation of Cdc25C as well as mitotic arrest were significantly attenuated by knockdown of check-point kinase 1 protein in both PC-3 and DU145 cells. On the other hand, depletion of checkpoint kinase 2 protein did not have any appreciable effect on G₂ or M phase arrest or Cdc25C phosphorylation caused by diallyl trisulfide. The lack of a role of checkpoint kinase 2 in diallyl trisulfide-induced phosphorylation of Cdc25C or G₂-M phase cell cycle arrest was confirmed using HCT-15 cells stably transfected with phosphorylation-deficient mutant (T68A mutant) of checkpoint kinase 2. In conclusion, the results of the present study suggest existence of a checkpoint kinase 1-dependent mechanism for diallyl trisulfide-induced mitotic arrest in human prostate cancer cells.

Received for publication, February 7, 2005 , and in revised form, June 3, 2005.

^* This work was supported in part by NCI, National Institutes of Health, United States Public Health Service Grants CA113363, CA101753, and CA076348 (to S. V. S.). 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.

To whom correspondence should be addressed: Hillman Cancer Center, Research Pavilion Suite 2.32A, University of Pittsburgh Cancer Institute, 5117 Center Ave., Pittsburgh, PA 15213. Tel.: 412-623-3263; Fax: 412-623-7828; E-mail: singhs{at}upmc.edu.

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