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Research Articles: Therapeutics, Targets, and Development

Proapoptotic ability of oncogenic H-Ras to facilitate apoptosis induced by histone deacetylase inhibitors in human cancer cells

Anticancer Molecular Oncology Laboratory, Department of Pathobiology College of Veterinary Medicine, The University of Tennessee, Knoxville, Tennessee

Requests for reprints: Hwa-Chain Robert Wang, Department of Pathobiology, College of Veterinary Medicine, The University of Tennessee, 2407 River Drive, Knoxville, TN 37996. Phone: 865-974-3846; Fax: 865-974-5616. E-mail: hcrwang{at}utk.edu

Abstract

More than 35% of human urinary bladder cancers involve oncogenic H-Ras activation. In addition to tumorigenic ability, oncogenic H-Ras possesses a novel proapoptotic ability to facilitate the induction of apoptosis by histone deacetylase inhibitors (HDACI). HDACIs are a new class of anticancer agents and are highly cytotoxic to transformed cells. To understand the connection between the selectivity of HDACIs on transformed cells and the proapoptotic ability of oncogenic H-Ras to facilitate HDACI-induced apoptosis, we introduced oncogenic H-Ras into urinary bladder J82 cancer cells to mimic an acquisition of the H-ras gene activation in tumor development. Expression of oncogenic H-Ras promoted J82 cells to acquire tumorigenic ability. Meanwhile, oncogenic H-Ras increased susceptibility of J82 cells to HDACIs, including FR901228 and trichostatin A, for inducing apoptosis. The caspase pathways, the B-Raf and extracellular signal-regulated kinase pathway, p21^Cip1 and p27^Kip1, and core histone contents are regulated differently by FR901228 in oncogenic H-Ras–expressed J82 cells than their counterparts in parental J82 cells, contributing to the increased susceptibility to the induction of selective apoptosis. Our results lead us to a suggestion that HDACIs activate the proapoptotic ability of oncogenic H-Ras, indicating a potential therapeutic value of this new class of anticancer agents in the control of human urinary bladder cancer that has progressed to acquire oncogenic H-Ras. [Mol Cancer Ther 2007;6(3):1099–111]

Grant support: The University of Tennessee, College of Veterinary Medicine, Center of Excellence in Livestock Diseases and Human Health (H-C.R. Wang).

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 9/19/06; revised 11/29/06; accepted 1/31/07.

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