This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Muenchen, H. J. Articles by Pienta, K. J. Search for Related Content PubMed PubMed Citation Articles by Muenchen, H. J. Articles by Pienta, K. J.

Tumor Necrosis Factor--induced Apoptosis in Prostate Cancer Cells through Inhibition of Nuclear Factor-B by an IB "Super-Repressor"¹

Department of Internal Medicine, Division of Hematology/Oncology [H. J. M., M. A. W., K. J. P.], Department of Animal Medicine, Division of Pathology, [D-L. L., E. T. K.], and Department of Surgery, Division of Urology [K. J. P.], University of Michigan, Ann Arbor, Michigan 48109

Prostate cancer patients experiencing a relapse in disease often express high serum tumor necrosis factor- (TNF-) levels. Many androgen-insensitive prostate cancer cells are TNF- insensitive because of the expression of antiapoptotic genes as part of the nuclear factor-B (NF-B) family of transcription factors. NF-B stimulates gene transcription when expressed in the nucleus; however, in resting cells, this nuclear import is prevented by association with the cytoplasmic inhibitor IB. This cytoplasmic retention of NF-B is uncoupled by many extracellular signals including low levels of TNF-. During normal cell activation, nuclear translocation of NF-B is preceded by phosphorylation and degradation of IB. When phosphorylation is blocked, IB remains intact, thereby blocking NF-B translocation to the nucleus and subsequent activation of antiapoptotic genes that cause TNF- insensitivity. We tested whether a "super-repressor" of NF-B activity could be transfected into prostate cancer cells and make them TNF- sensitive. PC-3 and LNCaP cells were stimulated with TNF- (10 ng/ml) for 24 h in the presence or absence of the IB "super-repressor" (p6R-IB_{S32A + S36A}). NF-B activity was measured by electrophoretic mobility shift assay and the steady state levels of the cytoplasmic IB protein were measured by Western blot. Secretory IL-6 and IL-6 mRNA were measured by ELISA. p6R-IB_{S32A + S36A} blocked the stimulation of NF-B activity by TNF- in prostate cancer cells. It also subsequently decreased IL-6 production by TNF-. We conclude that these data demonstrate that inhibition of NF-B selectively sensitizes previously insensitive prostate cancer cells to TNF-.

This article has been cited by other articles:

				M. B. Rettig, D. Heber, J. An, N. P. Seeram, J. Y. Rao, H. Liu, T. Klatte, A. Belldegrun, A. Moro, S. M. Henning, et al. Pomegranate extract inhibits androgen-independent prostate cancer growth through a nuclear factor-{kappa}B-dependent mechanism Mol. Cancer Ther., September 1, 2008; 7(9): 2662 - 2671. [Abstract] [Full Text] [PDF]

				A. Paone, D. Starace, R. Galli, F. Padula, P. De Cesaris, A. Filippini, E. Ziparo, and A. Riccioli Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-{alpha}-dependent mechanism Carcinogenesis, July 1, 2008; 29(7): 1334 - 1342. [Abstract] [Full Text] [PDF]

				L. Farhana, M. I. Dawson, and J. A. Fontana Apoptosis Induction by a Novel Retinoid-Related Molecule Requires Nuclear Factor-{kappa}B Activation Cancer Res., June 1, 2005; 65(11): 4909 - 4917. [Abstract] [Full Text] [PDF]

				C. Sweeney, L. Li, R. Shanmugam, P. Bhat-Nakshatri, V. Jayaprakasan, L. A. Baldridge, T. Gardner, M. Smith, H. Nakshatri, and L. Cheng Nuclear Factor-{kappa}B Is Constitutively Activated in Prostate Cancer In vitro and Is Overexpressed in Prostatic Intraepithelial Neoplasia and Adenocarcinoma of the Prostate Clin. Cancer Res., August 15, 2004; 10(16): 5501 - 5507. [Abstract] [Full Text] [PDF]

				C. N. Papandreou and C. J. Logothetis Bortezomib as a Potential Treatment for Prostate Cancer Cancer Res., August 1, 2004; 64(15): 5036 - 5043. [Abstract] [Full Text] [PDF]

				T. Lu, L. G. Burdelya, S. M. Swiatkowski, A. D. Boiko, P. H. Howe, G. R. Stark, and A. V. Gudkov Secreted transforming growth factor {beta}2 activates NF-{kappa}B, blocks apoptosis, and is essential for the survival of some tumor cells PNAS, May 4, 2004; 101(18): 7112 - 7117. [Abstract] [Full Text] [PDF]

				D. Chatterjee, Y. Bai, Z. Wang, S. Beach, S. Mott, R. Roy, C. Braastad, Y. Sun, A. Mukhopadhyay, B. B. Aggarwal, et al. RKIP Sensitizes Prostate and Breast Cancer Cells to Drug-induced Apoptosis J. Biol. Chem., April 23, 2004; 279(17): 17515 - 17523. [Abstract] [Full Text] [PDF]

				J. S. Ross, B. V. S. Kallakury, C. E. Sheehan, H. A. G. Fisher, R. P. Kaufman Jr., P. Kaur, K. Gray, and B. Stringer Expression of Nuclear Factor-{kappa}B and I{kappa}B{alpha} Proteins in Prostatic Adenocarcinomas: Correlation of Nuclear Factor-{kappa}B Immunoreactivity with Disease Recurrence Clin. Cancer Res., April 1, 2004; 10(7): 2466 - 2472. [Abstract] [Full Text] [PDF]

				J. An, Y.-P. Sun, J. Adams, M. Fisher, A. Belldegrun, and M. B. Rettig Drug Interactions between the Proteasome Inhibitor Bortezomib and Cytotoxic Chemotherapy, Tumor Necrosis Factor (TNF) {alpha}, and TNF-Related Apoptosis-Inducing Ligand in Prostate Cancer Clin. Cancer Res., October 1, 2003; 9(12): 4537 - 4545. [Abstract] [Full Text] [PDF]

				A. Parcellier, E. Schmitt, S. Gurbuxani, D. Seigneurin-Berny, A. Pance, A. Chantome, S. Plenchette, S. Khochbin, E. Solary, and C. Garrido HSP27 Is a Ubiquitin-Binding Protein Involved in I-{kappa}B{alpha} Proteasomal Degradation Mol. Cell. Biol., August 15, 2003; 23(16): 5790 - 5802. [Abstract] [Full Text] [PDF]

				E. Kikuchi, Y. Horiguchi, J. Nakashima, K. Kuroda, M. Oya, T. Ohigashi, N. Takahashi, Y. Shima, K. Umezawa, and M. Murai Suppression of Hormone-refractory Prostate Cancer by a Novel Nuclear Factor {kappa}B Inhibitor in Nude Mice Cancer Res., January 1, 2003; 63(1): 107 - 110. [Abstract] [Full Text] [PDF]

				R. G. Uzzo, P. Leavis, W. Hatch, V. L. Gabai, N. Dulin, N. Zvartau, and V. M. Kolenko Zinc Inhibits Nuclear Factor-{kappa}B Activation and Sensitizes Prostate Cancer Cells to Cytotoxic Agents Clin. Cancer Res., November 1, 2002; 8(11): 3579 - 3583. [Abstract] [Full Text] [PDF]

				C. D. Chen and C. L. Sawyers NF-{kappa}B Activates Prostate-Specific Antigen Expression and Is Upregulated in Androgen-Independent Prostate Cancer Mol. Cell. Biol., April 15, 2002; 22(8): 2862 - 2870. [Abstract] [Full Text] [PDF]

				P. Schotte, G. Van Loo, I. Carpentier, P. Vandenabeele, and R. Beyaert Lithium Sensitizes Tumor Cells in an NF-kappa B-independent Way to Caspase Activation and Apoptosis Induced by Tumor Necrosis Factor (TNF). EVIDENCE FOR A ROLE OF THE TNF RECEPTOR-ASSOCIATED DEATH DOMAIN PROTEIN J. Biol. Chem., July 6, 2001; 276(28): 25939 - 25945. [Abstract] [Full Text] [PDF]