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Research Articles: Therapeutics, Targets, and Development

Trichostatin A up-regulates p73 and induces Bax-dependent apoptosis in cisplatin-resistant ovarian cancer cells

¹ Department of Cellular and Developmental Biology, Sapienza University of Rome; ² Molecular Pathology Laboratory, Regina Elena Cancer Institute; ³ Gynecologic Oncology Unit, Catholic University of the Sacred Heart; and ⁴ Department of Dermatology University "Tor Vergata," Rome, Italy

Requests for reprints: Loretta Tuosto, Department of Cellular and Developmental Biology, Sapienza University of Rome, Via dei sardi 70, 00185-Rome, Italy. Phone: 39-6-49917595; Fax: 39-6-49917594. E-mail: loretta.tuosto{at}uniroma1.it

Abstract

Several studies in the last years evidenced that deregulation of proapoptotic and antiapoptotic pathways are key players in the onset and maintenance of chemoresistance in advanced ovarian cancers. To characterize the signaling events and molecules involved in the acquisition of cisplatin resistance, we used the human ovarian cancer cell line A2780 and its derivative cisplatin-resistant subline A2780 CIS. We found that the mitochondrial intrinsic apoptotic pathway, induced by cis-dichlorodiammineplatinum (CDDP) in A2780 wild-type cells, was compromised in the resistant subline CIS. The analysis of expression of proteins involved in mitochondria-dependent apoptosis revealed a role of Bax and p73 but not p53. Indeed, we found that CDDP treatment induced the up-regulation of p53 in both sensitive and resistant A2780 cell lines. By contrast, p73 and Bax expressions were compromised in resistant cells. Pretreatment of resistant A2780 CIS cells with the histone deacetylase inhibitor trichostatin A overcomes apoptosis resistance to CDDP by restoring both p73 and Bax but not p53 expression. Altogether, these data indicate that p73, but not p53, is involved in the regulation of apoptosis susceptibility to cisplatin in A2780 ovarian cancer cells and evidence a key contribution of histone deacetylase activation in the acquisition of chemotherapy resistance in human ovarian cancer cells. [Mol Cancer Ther 2008;7(6):1410–9]

Grant support: Italian Association for Cancer Research, Ministry of University and Research (MUR-PRIN), and "Istituto Pasteur-Fondazione Cenci Bolognetti," Sapienza University of Rome; "Fondazione Andrea Cesalpino," Policlinico Umberto I, Sapienza University (L. Tuosto).

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 1/ 8/08; revised 3/28/08; accepted 4/10/08.