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

Background: NF-kappa B is a transcription factor that promotes inhibition of apoptosis and resistance to chemotherapy. It is commonly believed that inhibition of NF-kappa B activity can increase sensitivity of cancer cells to chemotherapy. However, there is evidence that NF-kappa B activation can sensitize cells to apoptosis and that inhibition of NF-kappa B 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-kappa B is required for stimulation of apoptosis by chemotherapy. Results: Our 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-kappa B activity. In androgen-dependent LNCaP cells, Doc and 2ME2 treatment increased the low basal NF-kappa B activity, as determined by Western blot analysis of phospho-I kappa B alpha/p65, NF-kappa B promoter reporter assays, and p65 localization. Treatment of LNCaP cells with parthenolide, a pharmacologic inhibitor of NF-kappa B, or introduction of dominant-negative I kappa B alpha, or an shRNA specific for p65, a component of the NF-kappa B 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-kappa B 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-kappa B, 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-kappa B activity. Conclusions: Our data suggest that the combination of antimitotic drugs with NF-kappa B 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-kappa B, will universally enhance cell death in PC cells, notably in the aggressive, castration-resistant variety that does not respond to conventional therapies.