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

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.

Betulinic Acid Selectively Increases Protein Degradation and Enhances Prostate Cancer-Specific Apoptosis: Possible Role for Inhibition of Deubiquitinase Activity

“…S6). Our DUB assay results showed that BA treatment of LNCaP cells reduced DUB activity starting at 24 h. In contrast, treatment of LNCaP with 1 nM docetaxel, a dose that increased apoptotic cell death [28], had less effect on DUB activity (Fig. 6B).…”

“…1) as an agent that can enhance the sensitivity of PC cell lines to cell death when combined with antimitotic agents by increasing NF-κB activity, in part due to enhanced degradation of IκBα [27], [28]. To evaluate the in vivo therapeutic efficacy of BA, we utilized the TRAMP transgenic mouse model of PC [29], [30].…”

Aspirin Inhibits IKK-β-mediated Prostate Cancer Cell Invasion by Targeting Matrix Metalloproteinase-9 and Urokinase-Type Plasminogen Activator

“…The NF-κB luciferase reporter construct (NF-κB-Luc) containing four copies of NF-κB cis-acting elements linked to TATA box was cloned into pGL3 basic vector [24]. Cells were plated in 24-well plates, then the cells were co-transfected with NF-κB-Luc plasmid and the internal control plasmid renilla luciferase (pRL-TK) using transfection reagent Lipofectamine 2000 (Invitrogen, Carlsbad, CA) as described previously [25].…”

Oncolytic activity of canine distemper virus in canine mammary tubular adenocarcinoma cells

“…Even though activation of NF‐κB signalling is involved in some cell pro‐survival pathways, it is also implicated under some conditions in apoptotic induction . Several oncolytic viruses, such as reoviruses and Newcastle disease virus, have been reported to require activation of the NF‐κB signalling pathway for their induction of apoptosis in cancer cells .…”