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 Shukla, S. Articles by Gupta, S. Search for Related Content PubMed PubMed Citation Articles by Shukla, S. Articles by Gupta, S.

Suppression of Constitutive and Tumor Necrosis Factor -Induced Nuclear Factor (NF)-B Activation and Induction of Apoptosis by Apigenin in Human Prostate Carcinoma PC-3 Cells: Correlation with Down-Regulation of NF-B-Responsive Genes

¹ Department of Urology, The James & Eillen Dicke Research Laboratory, Case Western Reserve University; ² University Hospitals of Cleveland; and ³ Ireland Cancer Center, Cleveland, Ohio

Purpose: Development of androgen independence and resistance to apoptosis in prostate cancer are often correlated with high levels of serum tumor necrosis factor (TNF)- in these patients. The loss of sensitivity to TNF--induced apoptosis in androgen-insensitive prostate carcinoma cells is due in part to constitutive activation of Rel/nuclear factor (NF)-B transcription factors that regulate several cell survival and antiapoptotic genes. Our previous studies have demonstrated growth inhibitory and apoptotic effects of apigenin, a common plant flavonoid, in a variety of human prostate carcinoma cells. Here we examined whether apigenin is effective in inhibiting NF-B expression in androgen-insensitive human prostate carcinoma cells exhibiting high constitutive levels of NF-B.

Experimental Design: Using androgen-insensitive human prostate carcinoma PC-3 cells, the effect of apigenin was assessed on NF-B activation by electrophoretic mobility shift assay and reporter gene assay. Expression of NF-B subunits p65 and p50, IB, p-IB, in-beads kinase assay and NF-B-regulated genes were determined by Western blot analysis. Apoptosis was determined by annexin V/propidium iodide staining after fluorescence-activated cell-sorting analysis.

Results: Treatment of cells with 10–40-µM doses of apigenin inhibited DNA binding and reduced nuclear levels of the p65 and p50 subunits of NF-B. Apigenin inhibited IB degradation and IB phosphorylation and significantly decreased IKK kinase activity. Apigenin also inhibited TNF--induced activation of NF-B via the IB pathway, thereby sensitizing the cells to TNF--induced apoptosis. The inhibition of NF-B activation correlated with a decreased expression of NF-B-dependent reporter gene and suppressed expression of NF-B-regulated genes [specifically, Bcl2, cyclin D1, cyclooxygenase-2, matrix metalloproteinase 9, nitric oxide synthase-2 (NOS-2), and vascular endothelial growth factor].

Conclusions: Our results indicate that inhibition of NF-B by apigenin may lead to prostate cancer suppression by transcriptional repression of NF-B-responsive genes as well as selective sensitization of prostate carcinoma cells to TNF--induced apoptosis.

This article has been cited by other articles:

				S. Dhingra, A. K. Sharma, R. C. Arora, J. Slezak, and P. K. Singal IL-10 attenuates TNF-{alpha}-induced NF{kappa}B pathway activation and cardiomyocyte apoptosis Cardiovasc Res, April 1, 2009; 82(1): 59 - 66. [Abstract] [Full Text] [PDF]

				P. Kaur, S. Shukla, and S. Gupta Plant flavonoid apigenin inactivates Akt to trigger apoptosis in human prostate cancer: an in vitro and in vivo study Carcinogenesis, November 1, 2008; 29(11): 2210 - 2217. [Abstract] [Full Text] [PDF]

				M M Ceesay, B Vadher, B Tinwell, R Goderya, and E Sawicka Spontaneous remission of T lymphoblastic lymphoma J. Clin. Pathol., August 1, 2008; 61(8): 955 - 957. [Full Text] [PDF]

				X. Long, M. Fan, R. M. Bigsby, and K. P. Nephew Apigenin inhibits antiestrogen-resistant breast cancer cell growth through estrogen receptor-{alpha}-dependent and estrogen receptor-{alpha}-independent mechanisms Mol. Cancer Ther., July 1, 2008; 7(7): 2096 - 2108. [Abstract] [Full Text] [PDF]

				F.-M. Lin, L.-R. Chen, E.-H. Lin, F.-C. Ke, H.-Y. Chen, M.-J. Tsai, and P.-W. Hsiao Compounds from Wedelia chinensis synergistically suppress androgen activity and growth in prostate cancer cells Carcinogenesis, December 1, 2007; 28(12): 2521 - 2529. [Abstract] [Full Text] [PDF]

				D. Huang, M. Khoe, M. Befekadu, S. Chung, Y. Takata, D. Ilic, and M. Bryer-Ash Focal adhesion kinase mediates cell survival via NF-{kappa}B and ERK signaling pathways Am J Physiol Cell Physiol, April 1, 2007; 292(4): C1339 - C1352. [Abstract] [Full Text] [PDF]

				R. P Singh and R. Agarwal Mechanisms of action of novel agents for prostate cancer chemoprevention. Endocr. Relat. Cancer, September 1, 2006; 13(3): 751 - 778. [Abstract] [Full Text] [PDF]

				G. P. Collett and F. C. Campbell Overexpression of p65/RelA potentiates curcumin-induced apoptosis in HCT116 human colon cancer cells Carcinogenesis, June 1, 2006; 27(6): 1285 - 1291. [Abstract] [Full Text] [PDF]

				S. Shukla and S. Gupta Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft. Mol. Cancer Ther., April 1, 2006; 5(4): 843 - 852. [Abstract] [Full Text] [PDF]

				H. Hasegawa, Y. Yamada, K. Komiyama, M. Hayashi, M. Ishibashi, T. Yoshida, T. Sakai, T. Koyano, T.-S. Kam, K. Murata, et al. Dihydroflavonol BB-1, an extract of natural plant Blumea balsamifera, abrogates TRAIL resistance in leukemia cells Blood, January 15, 2006; 107(2): 679 - 688. [Abstract] [Full Text] [PDF]

				S C J P Gielen, L C M Kuhne, P C Ewing, L J Blok, and C W Burger Tamoxifen treatment for breast cancer enforces a distinct gene-expression profile on the human endometrium: an exploratory study Endocr. Relat. Cancer, December 1, 2005; 12(4): 1037 - 1049. [Abstract] [Full Text] [PDF]

				Y.-T. Huang, S.-L. Pan, J.-H. Guh, Y.-L. Chang, F.-Y. Lee, S.-C. Kuo, and C.-M. Teng YC-1 suppresses constitutive nuclear factor-{kappa}B activation and induces apoptosis in human prostate cancer cells Mol. Cancer Ther., October 1, 2005; 4(10): 1628 - 1635. [Abstract] [Full Text] [PDF]

				M. F. McCarty Targeting Multiple Signaling Pathways as a Strategy for Managing Prostate Cancer: Multifocal Signal Modulation Therapy Integr Cancer Ther, December 1, 2004; 3(4): 349 - 380. [Abstract] [PDF]