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Sensitization of prostate carcinoma cells to Apo2L/TRAIL by a Bcl-2 family protein inhibitor

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Abstract

Overexpression of anti-apoptotic Bcl-2 family proteins may play an important role in the aggressive behavior of prostate cancer cells and their resistance to therapy. The Bcl-2 homology 3 domain (BH3) is a uniquely important functional element within the pro-apoptotic class of the Bcl-2-related proteins, mediating their ability to dimerize with other Bcl-2-related proteins and promote apoptosis. The BH3 inhibitors (BH3Is) function by disrupting the interactions mediated by the BH3 domain between pro- and anti-apoptotic members of the Bcl-2 family and liberating more Bax/Bak to induce mitochondrial membrane permeabilization. LNCaP-derived C4-2 human prostate cancer cells are quite resistant to non-tagged, human recombinant soluble Apo2 ligand [Apo2L, also Tumor necrosis factor (TNF)-related apoptosis-inducing ligand, TRAIL], a tumor specific drug that is now in clinical trials. However, when Apo2L/TRAIL was combined with the Bcl-xL inhibitor, BH3I-2′, it induced apoptosis synergistically through activation of Caspase-8 and the proapoptotic Bcl-2 family member Bid, resulting in the activation of effector Caspase-3 and proteolytic cleavage of Poly(ADP-ribose) polymerase, events that were blocked by the pan-caspase inhibitor zVAD-fmk. Our data indicate that, in combination with the BH3 mimetic, BH3I-2′, Apo2L/TRAIL synergistically induces apoptosis in C4-2 human prostate cancer cells through both the extrinsic and intrinsic apoptotic pathways.

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Abbreviations

Apo2L:

Apo2 ligand

BH3I-2′:

3-iodo-5-chloro-N- [2-chloro-5-((4-chlorophenyl) sulphonyl) phenyl] -2-hydroxybenzamide

DR:

death receptor

MTS:

[3-(4,5-dimethylthiozol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium

PARP:

poly-ADP ribose polymerase

zVAD:

N-tert-butoxy-carbonyl-Val-Ala-Asp-fluoromethyl-ketone

TRAIL:

TNF-related apoptosis-inducing ligand.

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Author notes

  1. O. Bucur

    Present address: Department of Cellular and Molecular Medicine, “Carol Davila”, University of Medicine and Pharmacy, Bucharest, Romania

Authors and Affiliations

  1. Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, 44195

    S. Ray, O. Bucur & A. Almasan

  2. Department of Radiation Oncology, The Cleveland Clinic Foundation, Cleveland, Ohio, 44195

    A. Almasan

  3. Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, 44195

    A. Almasan

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Correspondence to A. Almasan.

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Ray, S., Bucur, O. & Almasan, A. Sensitization of prostate carcinoma cells to Apo2L/TRAIL by a Bcl-2 family protein inhibitor. Apoptosis 10, 1411–1418 (2005). https://doi.org/10.1007/s10495-005-2490-y

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