This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Agarwal, C. Articles by Agarwal, R. Search for Related Content PubMed PubMed Citation Articles by Agarwal, C. Articles by Agarwal, R. Related Collections Preclinical Intervention Preclinical Intervention: In Vitro: Drugs, Mechanisms

Research Articles: Therapeutics, Targets, and Development

Gallic acid causes inactivating phosphorylation of cdc25A/cdc25C-cdc2 via ATM-Chk2 activation, leading to cell cycle arrest, and induces apoptosis in human prostate carcinoma DU145 cells

¹ Department of Pharmaceutical Sciences, School of Pharmacy; and ² University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado

Requests for reprints: Chapla Agarwal, Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Box C238, Denver, CO 80262. Phone: 303-315-1382; Fax: 303-315-6281. E-mail: Chapla.Agarwal{at}uchsc.edu

Abstract

We recently reported that gallic acid is a major active agent responsible for grape seed extract activity in DU145 human prostate carcinoma cells. The present study was conducted to examine its efficacy and associated mechanism. Gallic acid treatment of DU145 cells resulted in a strong cell growth inhibition, cell cycle arrest, and apoptotic death in a dose- and time-dependent manner, together with a decrease in cyclin-dependent kinases and cyclins but strong induction in Cip1/p21. Additional mechanistic studies showed that gallic acid induces an early Tyr¹⁵ phosphorylation of cell division cycle 2 (cdc2). Further upstream, gallic acid also induced phosphorylation of both cdc25A and cdc25C via ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (Chk2) activation as a DNA damage response evidenced by increased phospho-histone 2AX (H2A.X) that is phosphorylated by ATM in response to DNA damage. Time kinetics of ATM phosphorylation, together with those of H2A.X and Chk2, was in accordance with an inactivating phosphorylation of cdc25A and cdc25C phosphatases and cdc2 kinase, suggesting that gallic acid increases cdc25A/C-cdc2 phosphorylation and thereby inactivation via ATM-Chk2 pathway following DNA damage that induces cell cycle arrest. Caffeine, an ATM/ataxia telangiectasia-rad3-related inhibitor, reversed gallic acid–caused ATM and H2A.X phosphorylation and cell cycle arrest, supporting the role of ATM pathway in gallic acid–induced cell cycle arrest. Additionally, gallic acid caused caspase-9, caspase-3, and poly(ADP)ribose polymerase cleavage, but pan-caspase inhibitor did not reverse apoptosis, suggesting an additional caspase-independent apoptotic mechanism. Together, this is the first report identifying gallic acid efficacy and associated mechanisms in an advanced and androgen-independent human prostate carcinoma DU145 cells, suggesting future in vivo efficacy studies with this agent in preclinical prostate cancer models. [Mol Cancer Ther 2006;5(12):3294–302]

Grant support: National Cancer Institute/NIH grant CA91883 (C. Agarwal).

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.

Received 8/10/06; revised 10/ 6/06; accepted 10/30/06.

This article has been cited by other articles:

				J. L. Marlowe, Y. Fan, X. Chang, L. Peng, E. S. Knudsen, Y. Xia, and A. Puga The Aryl Hydrocarbon Receptor Binds to E2F1 and Inhibits E2F1-induced Apoptosis Mol. Biol. Cell, August 1, 2008; 19(8): 3263 - 3271. [Abstract] [Full Text] [PDF]

				K. Raina, S. Rajamanickam, G. Deep, M. Singh, R. Agarwal, and C. Agarwal Chemopreventive effects of oral gallic acid feeding on tumor growth and progression in TRAMP mice Mol. Cancer Ther., May 1, 2008; 7(5): 1258 - 1267. [Abstract] [Full Text] [PDF]

				L. Fini, E. Hotchkiss, V. Fogliano, G. Graziani, M. Romano, E. B. De Vol, H. Qin, M. Selgrad, C.R. Boland, and L. Ricciardiello Chemopreventive properties of pinoresinol-rich olive oil involve a selective activation of the ATM-p53 cascade in colon cancer cell lines Carcinogenesis, January 1, 2008; 29(1): 139 - 146. [Abstract] [Full Text] [PDF]

				K. Raina, R. P. Singh, R. Agarwal, and C. Agarwal Oral Grape Seed Extract Inhibits Prostate Tumor Growth and Progression in TRAMP Mice Cancer Res., June 15, 2007; 67(12): 5976 - 5982. [Abstract] [Full Text] [PDF]