Cancer Therapy
SAHA-sensitized prostate cancer cells to TNFα-related apoptosis-inducing ligand (TRAIL): Mechanisms leading to synergistic apoptosis
Vijayabaskar Lakshmikanthan,
Ismail Kaddour-Djebbar,
Ronald W. Lewis,
M. Vijay Kumar,
Vijayabaskar Lakshmikanthan
Department of Surgery, Medical College of Georgia, Augusta, GA
Search for more papers by this authorIsmail Kaddour-Djebbar
Department of Surgery, Medical College of Georgia, Augusta, GA
Search for more papers by this authorRonald W. Lewis
Department of Surgery, Medical College of Georgia, Augusta, GA
Search for more papers by this authorCorresponding Author
M. Vijay Kumar
Department of Surgery, Medical College of Georgia, Augusta, GA
VA Medical Center, Augusta, GA
Fax: 706 721-2548 or 706 823 2254.
Section of Urology, Department of Surgery, 15th Street, Medical College of Georgia, Augusta, GA 30912Search for more papers by this authorVijayabaskar Lakshmikanthan,
Ismail Kaddour-Djebbar,
Ronald W. Lewis,
M. Vijay Kumar,
Vijayabaskar Lakshmikanthan
Department of Surgery, Medical College of Georgia, Augusta, GA
Search for more papers by this authorIsmail Kaddour-Djebbar
Department of Surgery, Medical College of Georgia, Augusta, GA
Search for more papers by this authorRonald W. Lewis
Department of Surgery, Medical College of Georgia, Augusta, GA
Search for more papers by this authorCorresponding Author
M. Vijay Kumar
Department of Surgery, Medical College of Georgia, Augusta, GA
VA Medical Center, Augusta, GA
Fax: 706 721-2548 or 706 823 2254.
Section of Urology, Department of Surgery, 15th Street, Medical College of Georgia, Augusta, GA 30912Search for more papers by this authorAbstract
Treatment of cancer cells with histone deacetylase inhibitors (HDACi) such as suberolylanilide hydroxamic acid (SAHA) activates genes that promote apoptosis. To enhance proapoptotic efficiency, SAHA has been used in combination with radiation, kinase inhibitors and cytotoxic drugs. Although several prostate cells respond to TNFα-Related Apoptosis-Inducing Ligand (TRAIL), LNCaP are resistant. This model system was utilized to examine the advantages of combined treatment with SAHA and TRAIL. In LNCaP cells, TRAIL induced synergistic apoptosis when combined with even with the lowest dose SAHA. Treatment with caspase inhibitor confirmed that SAHA-induced apoptosis was mediated through caspases. In addition to induction of apoptosis, SAHA and TRAIL decreased the levels of proapoptotic proteins IKKα, IKKβ and IKKγ, suggesting that SAHA treatment may reduce the activity of NFκB. However, assay for NFκB luciferase reporter activity showed highly significant increase in SAHA-treated cells, supporting earlier suggestions that HDACi promotes NFκB transcriptional activity. Further analyses to determine the mechanisms by which the combination of SAHA and TRAIL led to synergistic apoptosis indicated that the apoptotic response of LNCaP is due to a complex regulation of death receptor pathway and alterations of NFκB activity at several regulatory steps. © 2006 Wiley-Liss, Inc.
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