Abstract
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.
Highlights
NF-κB, originally discovered as a transcription factor that regulates the immune system, is known to be widely expressed in almost all cells and mediates multiple signaling pathways including cell proliferation and survival [1]
The nucleolus is normally disassembled during mitosis and reassembled after cell division [39]. These results suggest that in LNCaP cells treated with antimitotic drugs, p65 can localize to the nucleolus, which has previously been shown to be important in increasing apoptosis in colon cancer cells treated with aspirin [38]
Betulinic Acid (BA), an NF-κB Activator, Stimulates Cell Death in All Prostate Cancer Cells Treated with Antimitotic Drugs Our results showed that the NF-κB inhibitor parthenolide antagonized apoptosis mediated by antimitotic drugs in LNCaP and LN-AI cells
Summary
NF-κB, originally discovered as a transcription factor that regulates the immune system, is known to be widely expressed in almost all cells and mediates multiple signaling pathways including cell proliferation and survival [1]. Activation of the NF-κB pathway by a variety of inducers including cytokines, growth factors, UV light and DNAdamaging drugs often occurs by increasing the phosphorylation of IκBα by the IκB kinase (IKK) complex. This results in ubiquitination and rapid degradation of IκBα by the role of NF-κB in cancer progression and in anti-cancer therapeutics is complex, as there is evidence to suggest that NF-κB activation can sensitize cells to apoptosis [5,6]. It is not clear in the different cell types (androgen-dependent and castrationresistant) if activation or inhibition of NF-κB is required for stimulation of apoptosis by chemotherapy
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