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J. Biol. Chem., Vol. 280, Issue 49, 41047-41056, December 9, 2005

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Pretreatment of Acetylsalicylic Acid Promotes Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis by Down-regulating BCL-2 Gene Expression^*

Ki M. Kim, Jae J. Song, Jee Young An, Yong Tae Kwon, and Yong J. Lee1

From the Department of Surgery and Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213 and Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania 15261

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to be selective in the induction of apoptosis in cancer cells with minimal toxicity to normal tissues. However, not all cancers are sensitive to TRAIL-mediated apoptosis. Thus, TRAIL-resistant cancer cells must be sensitized first to become responsive to TRAIL. In this study, we observed that pretreatment by acetylsalicylic acid (ASA) augmented TRAIL-induced apoptotic death in human prostate adenocarcinoma LNCaP and human colorectal carcinoma CX-1 cells. Western blot analysis showed that pretreatment of ASA followed by TRAIL treatment activated caspases (8, 9, and 3) and cleaved poly(ADP-ribose) polymerase, the hallmark feature of apoptosis. Most interestingly, at least 12 h of pretreatment with ASA was prerequisite for promoting TRAIL-induced apoptosis and was related to down-regulation of BCL-2. Biochemical analysis revealed that ASA inhibited NF-B activity, which is known to regulate BCL-2 gene expression, by dephosphorylating IB- and inhibiting IKK activity but not by affecting the HER-2/neu phosphatidylinositol 3-kinase-Akt signal pathway. Overexpression of BCL-2 suppressed the promotive effect of ASA on TRAIL-induced apoptosis and changes in mitochondrial membrane potential. Taken together, our studies suggested that ASA-promoted TRAIL cytotoxicity is mediated through down-regulating BCL-2 and by decreasing mitochondrial membrane potential.

Received for publication, April 5, 2005 , and in revised form, September 19, 2005.

^* This work was supported by NCI Grants CA95191 and CA96989 from the National Institutes of Health, the Elsa U. Pardee Foundation, The Pittsburgh Foundation, Department of Defense Prostate Program Fund PC020530, and Department of Defense Prostate Traineeship PC040833. 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: Dept. of Surgery, University of Pittsburgh, Hillman Cancer Center 1.19, 5117 Centre Ave., Rm. 1.19, Pittsburgh, PA 15213. Tel.: 412-623-3268; Fax: 412-623-1415; E-mail: leeyj{at}msx.upmc.edu.

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