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Cell Cycle, Cell Death, and Senescence

Overexpression of BAD Potentiates Sensitivity to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Treatment in the Prostatic Carcinoma Cell Line LNCaP¹

Departments of ¹ Pathology, ² Urology, and ³ Epidemiology, The University of Iowa, Iowa City, IA; and
⁴ Department of Internal Medicine, Division of Hematology/Oncology, Virginia Commonwealth University, Richmond, VA

Requests for reprints: Michael B. Cohen, Department of Pathology, The University of Iowa, 200 Hawkins Drive, 1170 ML, Iowa City, IA 52242-1087. Phone: (319) 335-8232; Fax: (319) 335-8916. E-mail: michael-cohen{at}uiowa.edu

Here we show that LNCaP, which is resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, becomes sensitive to TRAIL after overexpression of full-length, wild-type BAD (BAD WT). TRAIL induces caspase-dependent cleavage of BAD WT that results in generation of a M_r 15,000 protein. LNCaP stably expressing truncated BAD (tBAD) and cells expressing mutated BAD at the caspase cleavage site were less sensitive to TRAIL treatment when compared to LNCaP expressing BAD WT. Cytochrome c and Smac/DIABLO release from mitochondria into cytosol was found after TRAIL treatment only in cells overexpressing BAD WT. Furthermore, differences in phosphorylation of serine residues for BAD WT and tBAD were identified. BAD WT was phosphorylated at positions S136 and S155, whereas tBAD was phosphorylated at positions S112, S136, and S155. LNCaP stably expressing BAD mutated at serine 112 to alanine was less sensitive to TRAIL treatment when compared to LNCaP expressing BAD WT. Lastly, recombinant BAD cleaved by caspase-3 is a more potent inducer of cytochrome c and Smac/DIABLO release than BAD WT. In summary, BAD-mediated sensitivity of LNCaP to TRAIL depends on the phosphorylation status of BAD WT and tBAD.

Key Words: BAD • prostatic carcinoma • TRAIL • apoptosis

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