This Article Full Text Full Text (PDF) All Versions of this Article: 28/2/282    most recent Author Manuscript (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 Benitez, D. A. Articles by Castellón, E. A. Search for Related Content PubMed PubMed Citation Articles by Benitez, D. A. Articles by Castellón, E. A.

Mechanisms Involved in Resveratrol-Induced Apoptosis and Cell Cycle Arrest in Prostate Cancer–Derived Cell Lines

EULALIA POZO-GUISADO

ALBERTO ALVAREZ-BARRIENTOS

PEDRO M. FERNANDEZ-SALGUERO

From the ^* Laboratorio de Andrología Celular y Molecular, Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile; the Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, Badajoz, Spain; and the Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.

Correspondence to: Dr Enrique A Castellón, Laboratory of Cell and Molecular Andrology, Physiology and Biophysics Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, PO Box 70005, Santiago-7, Chile (e-mail: ecastell{at}med.uchile.cl).

Resveratrol is a polyphenol found at high concentrations in grapes and red wine with reported anticarcinogenic effects. We studied the molecular mechanism of resveratrol-induced apoptosis and proliferation arrest in prostate derived cells PZ-HPV-7 (nontumorigenic line), LNCaP (androgen-sensitive cancer line), and PC-3 (androgen-insensitive cancer line). Apoptosis and cell cycle distribution were evaluated by flow cytometry and proliferation by MTT assay and direct cell counting. Caspases, bax, bcl-2, cyclins, Cdks, p53, p21, and p27 were measured by Western blot and kinase activities of cyclin/Cdk complexes by immunoprecipitation followed by kinase assays with appropriate substrates. Resveratrol induced a decrease in proliferation rates and an increase in apoptosis in cancer cell lines in a dose- and time-dependent manner. These effects were coincident with cell accumulation at the G0/G1 phase. In LNCaP and PC-3, the apoptosis induced by resveratrol was mediated by activation of caspases 9 and 3 and a change in the ratio of bax/bcl-2. Expressions of cyclin D1, E, and Cdk4 as well as cyclin D1/Cdk4 kinase activity were reduced by resveratrol only in LNCaP cells. In contrast, cyclin B and Cdk1 expression and cyclin B/Cdk1 kinase activity were decreased in both cell lines in the presence of resveratrol. However, modulator proteins p53, p21, and p27 were increased by resveratrol only in LNCaP cells. These effects probably result in the observed proliferation arrest and disruption of cell cycle control. In addition, the specific differences found between LNCaP and PC-3 suggest that resveratrol acts through different mechanisms upon the androgen or estrogen receptor cell status.

     Key words: Cyclins/Cdk complexes, androgen sensitivity, caspases, p53, p21

This article has been cited by other articles:

				T.-c. Hsieh, C.-J. Yang, C.-Y. Lin, Y.-S. Lee, and J. M. Wu Control of stability of cyclin D1 by quinone reductase 2 in CWR22Rv1 prostate cancer cells Carcinogenesis, February 7, 2012; (2012) bgs016v2. [Abstract] [Full Text] [PDF]

				L. KAI and A. S. LEVENSON Combination of Resveratrol and Antiandrogen Flutamide Has Synergistic Effect on Androgen Receptor Inhibition in Prostate Cancer Cells Anticancer Res, October 1, 2011; 31(10): 3323 - 3330. [Abstract] [Full Text] [PDF]

				E. J. Calabrese, M. P. Mattson, and V. Calabrese Resveratrol commonly displays hormesis: Occurrence and biomedical significance Human and Experimental Toxicology, December 1, 2010; 29(12): 980 - 1015. [Abstract] [PDF]

				L. Brizuela, A. Dayon, N. Doumerc, I. Ader, M. Golzio, J.-C. Izard, Y. Hara, B. Malavaud, and O. Cuvillier The sphingosine kinase-1 survival pathway is a molecular target for the tumor-suppressive tea and wine polyphenols in prostate cancer FASEB J, October 1, 2010; 24(10): 3882 - 3894. [Abstract] [Full Text] [PDF]

				H. Francis, G. Alpini, and S. DeMorrow Recent advances in the regulation of cholangiocarcinoma growth Am J Physiol Gastrointest Liver Physiol, July 1, 2010; 299(1): G1 - G9. [Abstract] [Full Text] [PDF]

				D. H. Wong, J. A. Villanueva, A. B. Cress, and A. J. Duleba Effects of resveratrol on proliferation and apoptosis in rat ovarian theca-interstitial cells Mol. Hum. Reprod., April 1, 2010; 16(4): 251 - 259. [Abstract] [Full Text] [PDF]

				N. Khan, V. M. Adhami, and H. Mukhtar Apoptosis by dietary agents for prevention and treatment of prostate cancer Endocr. Relat. Cancer, January 29, 2010; 17(1): R39 - R52. [Abstract] [Full Text] [PDF]

				H. Y. CHOI, S. A. CHONG, and M. J. NAM Resveratrol Induces Apoptosis in Human SK-HEP-1 Hepatic Cancer Cells Cancer Genomics Proteomics, September 1, 2009; 6(5): 263 - 268. [Abstract] [Full Text] [PDF]