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First published on September 11, 2007; DOI: 10.1124/mol.107.039610

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Received for publication July 3, 2007.
Revised September 10, 2007.
Accepted for publication September 11, 2007.

Aspirin Enhances TRAIL-Mediated Apoptosis in Hormone Refractory Prostate Cancer Cells through Survivin Downregulation

Jinsang Yoo 1 Yong Lee 2*

1 University of Pittsburgh 2 University of Pittsburgh, Cancer Institute

* Address correspondence to: E-mail: leeyj{at}msx.upmc.edu

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent because of its tumor selectivity. TRAIL is known to induce apoptosis in cancer cells but spare most normal cells. In this study, we examined whether acetylsalicylic acid (ASA), so called aspirin, enhances TRAIL-induced apoptosis in androgen-dependent LNCaP and androgen-independent LNCaP derived prostate cancer cells. To evaluate the cell death effects of TRAIL in combination with ASA on tumor cells, we performed DNA fragmentation assay, and immunoblot analysis for PARP-1, caspases and antiapoptotic proteins. We observed that ASA promoted TRAIL-induced apoptotic death in both LNCaP and its derived cells (C4, C4-2, and C4-2B). These enhancements of TRAIL effect were related to decrease in survivin protein expression by pretreatment with ASA. We also confirmed that knockdown in survivin expression by transfecting survivin siRNA increased TRAIL-induced apoptosis. To study the mechanism of survivin downregulation, we determined the levels of mRNA and the activities of survivin promoter in the ASA treated and untreated cells. Reduction of the intracellular levels of survivin protein was due to decrease in transcriptional activity. Data from electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) analyses revealed that ASA inhibited the transcription factor E2F-1 binding activity to the survivin promoter region, which is known to regulate survivin gene transcription. Taken together, our studies suggested that ASA-promoted TRAIL cytotoxicity is mediated through down-regulating survivin and the downregulation of survivin is due to inhibition of E2F-1 binding activity to the survivin promoter region.


Key words: Transcriptional coactivators, Promoter analysis, Mechanisms of cell killing/apoptosis, Metastasis


This article has been cited by other articles:


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M. Lu, A. Strohecker, F. Chen, T. Kwan, J. Bosman, V. C. Jordan, and V. L. Cryns
Aspirin Sensitizes Cancer Cells to TRAIL-Induced Apoptosis by Reducing Survivin Levels
Clin. Cancer Res., May 15, 2008; 14(10): 3168 - 3176.
[Abstract] [Full Text] [PDF]


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