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Resveratrol-induced apoptosis in MCF-7 human breast cancer cells involves a caspase-independent mechanism with downregulation of Bcl-2 and NF-kappaB.
Int J Cancer. 2005 May 20; 115(1):74-84.IJ

Abstract

Resveratrol (RES), a chemopreventive molecule, inhibits the proliferation of tumor cells of different etiologies. We previously showed that RES alters the cell cycle and induces apoptosis in MCF-7 breast tumor cells by interfering with the estrogen receptor (ERaalpha)-dependent phosphoinositide 3-kinase (PI3K) pathway. Here, we analyzed signaling downstream of PI3K, to understand the mechanisms of RES-induced apoptosis. Apoptotic death by RES in MCF-7 was mediated by Bcl-2 downregulation since overexpression of this protein abolished apoptosis. Decreased Bcl-2 levels were not related to cytochrome c release, activation of caspases 3/8 or poly(ADP-ribose) polymerase proteolysis. However, RES decreased mitochondrial membrane potential and increased reactive oxygen species and nitric oxide production. NF-kappaB, a regulator of Bcl-2 expression, and calpain protease activity, a regulator of NF-kappaB, were both inhibited by RES. The patterns for NF-kappaB and calpain activities followed that of PI3K and were inhibited by LY294002. NF-kappaB inhibition coincided with diminished MMP-9 activity and cell migration. These data suggest that RES-induced apoptosis in MCF-7 could involve an oxidative, caspase-independent mechanism, whereby inhibition of PI3K signaling converges to Bcl-2 through NF-kappaB and calpain protease activity. Therefore, Bcl-2 and NF-kappaB could be considered potential targets for the chemopreventive activity of RES in estrogen-responsive tumor cells.

Authors+Show Affiliations

Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, Badajoz, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15688415

Citation

Pozo-Guisado, Eulalia, et al. "Resveratrol-induced Apoptosis in MCF-7 Human Breast Cancer Cells Involves a Caspase-independent Mechanism With Downregulation of Bcl-2 and NF-kappaB." International Journal of Cancer, vol. 115, no. 1, 2005, pp. 74-84.
Pozo-Guisado E, Merino JM, Mulero-Navarro S, et al. Resveratrol-induced apoptosis in MCF-7 human breast cancer cells involves a caspase-independent mechanism with downregulation of Bcl-2 and NF-kappaB. Int J Cancer. 2005;115(1):74-84.
Pozo-Guisado, E., Merino, J. M., Mulero-Navarro, S., Lorenzo-Benayas, M. J., Centeno, F., Alvarez-Barrientos, A., Fernandez-Salguero, P. M., & Salguero, P. M. (2005). Resveratrol-induced apoptosis in MCF-7 human breast cancer cells involves a caspase-independent mechanism with downregulation of Bcl-2 and NF-kappaB. International Journal of Cancer, 115(1), 74-84.
Pozo-Guisado E, et al. Resveratrol-induced Apoptosis in MCF-7 Human Breast Cancer Cells Involves a Caspase-independent Mechanism With Downregulation of Bcl-2 and NF-kappaB. Int J Cancer. 2005 May 20;115(1):74-84. PubMed PMID: 15688415.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Resveratrol-induced apoptosis in MCF-7 human breast cancer cells involves a caspase-independent mechanism with downregulation of Bcl-2 and NF-kappaB. AU - Pozo-Guisado,Eulalia, AU - Merino,Jaime M, AU - Mulero-Navarro,Sonia, AU - Lorenzo-Benayas,M Jesús, AU - Centeno,Francisco, AU - Alvarez-Barrientos,Alberto, AU - Fernandez-Salguero,Pedro M, AU - Salguero,Pedro M Fernandez, PY - 2005/2/3/pubmed PY - 2005/6/1/medline PY - 2005/2/3/entrez SP - 74 EP - 84 JF - International journal of cancer JO - Int. J. Cancer VL - 115 IS - 1 N2 - Resveratrol (RES), a chemopreventive molecule, inhibits the proliferation of tumor cells of different etiologies. We previously showed that RES alters the cell cycle and induces apoptosis in MCF-7 breast tumor cells by interfering with the estrogen receptor (ERaalpha)-dependent phosphoinositide 3-kinase (PI3K) pathway. Here, we analyzed signaling downstream of PI3K, to understand the mechanisms of RES-induced apoptosis. Apoptotic death by RES in MCF-7 was mediated by Bcl-2 downregulation since overexpression of this protein abolished apoptosis. Decreased Bcl-2 levels were not related to cytochrome c release, activation of caspases 3/8 or poly(ADP-ribose) polymerase proteolysis. However, RES decreased mitochondrial membrane potential and increased reactive oxygen species and nitric oxide production. NF-kappaB, a regulator of Bcl-2 expression, and calpain protease activity, a regulator of NF-kappaB, were both inhibited by RES. The patterns for NF-kappaB and calpain activities followed that of PI3K and were inhibited by LY294002. NF-kappaB inhibition coincided with diminished MMP-9 activity and cell migration. These data suggest that RES-induced apoptosis in MCF-7 could involve an oxidative, caspase-independent mechanism, whereby inhibition of PI3K signaling converges to Bcl-2 through NF-kappaB and calpain protease activity. Therefore, Bcl-2 and NF-kappaB could be considered potential targets for the chemopreventive activity of RES in estrogen-responsive tumor cells. SN - 0020-7136 UR - https://www.unboundmedicine.com/medline/citation/15688415/Resveratrol_induced_apoptosis_in_MCF_7_human_breast_cancer_cells_involves_a_caspase_independent_mechanism_with_downregulation_of_Bcl_2_and_NF_kappaB_ L2 - https://doi.org/10.1002/ijc.20856 DB - PRIME DP - Unbound Medicine ER -