Tags

Type your tag names separated by a space and hit enter

Targeting the NF-kappa B pathway in estrogen receptor negative MDA-MB-231 breast cancer cells using small inhibitory RNAs.
J Cell Biochem. 2006 May 01; 98(1):221-33.JC

Abstract

Cancer cells in order to survive are often mutated to block apoptosis. One chemotherapeutic option is the re-establishment of apoptosis. An example of such a therapy is the PKC inhibitor Gö6976, which activates apoptosis and shrinks in vivo tumors in estrogen receptor-negative breast cancers. We proposed as a mechanism blockage of activation of the transcription factor NF-kappaB, which is anti-apoptotic and often elevated in cancers. Over recent years, questions have arisen regarding the specificity of these "small-molecule inhibitors." We have therefore explored the role of NF-kappaB inhibition in MDA-MB-231 breast cancer cells using small inhibitory RNAs (siRNA). siRNAs designed against NF-kappaB protein p65 (RelA) and IKKalpha, IKKbeta, and IKKgamma, strongly decreased the target proteins. But, unlike Gö6976, they did not decrease basal NF-kappaB or cause apoptosis. In particular, the decrease in p65 protein had no effects on apoptosis or cell proliferation, thus questioning the importance of NF-kappaB alone in the maintenance of these cells. Furthermore, the proteasome inhibitor MG-132 caused loss of IkappaBalpha, and an increase of it is phosphorylated form, but basal NF-kappaB was unchanged, whilst activation of NF-kappaB by TNFalpha was completely inhibited, suggesting that MG-132 activity is independent of constitutive NF-kappaB activation. We ascribe these differences to the specificity of inhibition by siRNAs as compared to the well-known non-specificity of small-molecule inhibitors. We conclude that the mutations in these cancer cells made them resistant to apoptosis, by elevating their NF-kappaB and activating other basal pathways that are blocked by Gö6976 but not by IKK and p65 siRNAs.

Authors+Show Affiliations

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.No affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

16408291

Citation

Monks, Noel R., and Arthur B. Pardee. "Targeting the NF-kappa B Pathway in Estrogen Receptor Negative MDA-MB-231 Breast Cancer Cells Using Small Inhibitory RNAs." Journal of Cellular Biochemistry, vol. 98, no. 1, 2006, pp. 221-33.
Monks NR, Pardee AB. Targeting the NF-kappa B pathway in estrogen receptor negative MDA-MB-231 breast cancer cells using small inhibitory RNAs. J Cell Biochem. 2006;98(1):221-33.
Monks, N. R., & Pardee, A. B. (2006). Targeting the NF-kappa B pathway in estrogen receptor negative MDA-MB-231 breast cancer cells using small inhibitory RNAs. Journal of Cellular Biochemistry, 98(1), 221-33.
Monks NR, Pardee AB. Targeting the NF-kappa B Pathway in Estrogen Receptor Negative MDA-MB-231 Breast Cancer Cells Using Small Inhibitory RNAs. J Cell Biochem. 2006 May 1;98(1):221-33. PubMed PMID: 16408291.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeting the NF-kappa B pathway in estrogen receptor negative MDA-MB-231 breast cancer cells using small inhibitory RNAs. AU - Monks,Noel R, AU - Pardee,Arthur B, PY - 2006/1/13/pubmed PY - 2009/5/30/medline PY - 2006/1/13/entrez SP - 221 EP - 33 JF - Journal of cellular biochemistry JO - J Cell Biochem VL - 98 IS - 1 N2 - Cancer cells in order to survive are often mutated to block apoptosis. One chemotherapeutic option is the re-establishment of apoptosis. An example of such a therapy is the PKC inhibitor Gö6976, which activates apoptosis and shrinks in vivo tumors in estrogen receptor-negative breast cancers. We proposed as a mechanism blockage of activation of the transcription factor NF-kappaB, which is anti-apoptotic and often elevated in cancers. Over recent years, questions have arisen regarding the specificity of these "small-molecule inhibitors." We have therefore explored the role of NF-kappaB inhibition in MDA-MB-231 breast cancer cells using small inhibitory RNAs (siRNA). siRNAs designed against NF-kappaB protein p65 (RelA) and IKKalpha, IKKbeta, and IKKgamma, strongly decreased the target proteins. But, unlike Gö6976, they did not decrease basal NF-kappaB or cause apoptosis. In particular, the decrease in p65 protein had no effects on apoptosis or cell proliferation, thus questioning the importance of NF-kappaB alone in the maintenance of these cells. Furthermore, the proteasome inhibitor MG-132 caused loss of IkappaBalpha, and an increase of it is phosphorylated form, but basal NF-kappaB was unchanged, whilst activation of NF-kappaB by TNFalpha was completely inhibited, suggesting that MG-132 activity is independent of constitutive NF-kappaB activation. We ascribe these differences to the specificity of inhibition by siRNAs as compared to the well-known non-specificity of small-molecule inhibitors. We conclude that the mutations in these cancer cells made them resistant to apoptosis, by elevating their NF-kappaB and activating other basal pathways that are blocked by Gö6976 but not by IKK and p65 siRNAs. SN - 0730-2312 UR - https://www.unboundmedicine.com/medline/citation/16408291/Targeting_the_NF_kappa_B_pathway_in_estrogen_receptor_negative_MDA_MB_231_breast_cancer_cells_using_small_inhibitory_RNAs_ L2 - https://doi.org/10.1002/jcb.20789 DB - PRIME DP - Unbound Medicine ER -