NF-κB activation enhances cell death by antimitotic drugs in human prostate cancer cells

Molecular Cancer

Research

Priyamvada Rai¹  Alicia de las Pozas²  Ricardo Parrondo²  Teresita Reiner²  Carlos Perez-Stable³ 

[1] Division of Gerontology & Geriatric Medicine, Department of Medicine, University of Miami Miller School of Medicine, 3136, Miami, FL, USA;Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 33136, Miami, FL, USA;Geriatric Research, Education, and Clinical Center and Research Service, Bruce W. Carter Veterans Affairs Medical Center, 33125, Miami, FL, USA;Geriatric Research, Education, and Clinical Center and Research Service, Bruce W. Carter Veterans Affairs Medical Center, 33125, Miami, FL, USA;Division of Gerontology & Geriatric Medicine, Department of Medicine, University of Miami Miller School of Medicine, 3136, Miami, FL, USA;Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 33136, Miami, FL, USA;

关键词: Prostate Cancer Cell;    LNCaP Cell;    DU145 Cell;    Betulinic Acid;    Parthenolide;   

DOI  :  10.1186/1476-4598-9-182

 received in 2009-09-21, accepted in 2010-07-09,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundNF-κB is a transcription factor that promotes inhibition of apoptosis and resistance to chemotherapy. It is commonly believed that inhibition of NF-κB activity can increase sensitivity of cancer cells to chemotherapy. However, there is evidence that NF-κB activation can sensitize cells to apoptosis and that inhibition of NF-κB results in resistance to chemotherapy. In prostate cancer, it is not clear in the different cell types (androgen-dependent and castration-resistant) if activation or inhibition of NF-κB is required for stimulation of apoptosis by chemotherapy.ResultsOur data indicate that the response of prostate cancer (PC) cells to the antimitotic drugs docetaxel (Doc) and 2-methoxyestradiol (2ME2) is dependent on the levels of NF-κB activity. In androgen-dependent LNCaP cells, Doc and 2ME2 treatment increased the low basal NF-κB activity, as determined by Western blot analysis of phospho-IκBα/p65, NF-κB promoter reporter assays, and p65 localization. Treatment of LNCaP cells with parthenolide, a pharmacologic inhibitor of NF-κB, or introduction of dominant-negative IκBα, or an shRNA specific for p65, a component of the NF-κB heterodimer, blocked apoptosis induced by Doc and 2ME2. In castration-resistant DU145 and PC3 cells, Doc and 2ME2 had little effect on the high basal NF-κB activity and addition of parthenolide did not enhance cell death. However, the combination of Doc or 2ME2 with betulinic acid (BA), a triterpenoid that activates NF-κB, stimulated apoptosis in LNCaP and non-apoptotic cell death in DU145 and PC3 cells. Increased sensitivity to cell death mediated by the Doc or 2ME2 + BA combination is likely due to increased NF-κB activity.ConclusionsOur data suggest that the combination of antimitotic drugs with NF-κB inhibitors will have antagonistic effects in a common type of PC cell typical of LNCaP. However, combination strategies utilizing antimitotic drugs with BA, an activator of NF-κB, will universally enhance cell death in PC cells, notably in the aggressive, castration-resistant variety that does not respond to conventional therapies.

【 授权许可】

Unknown   
© Parrondo et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.