NF-kappaB activation enhances cell death by antimitotic drugs in human prostate cancer cells.
BACKGROUND
NF-kappaB is a transcription factor that promotes inhibition of apoptosis and resistance to chemotherapy. It is commonly believed that inhibition of NF-kappaB activity can increase sensitivity of cancer cells to chemotherapy. However, there is evidence that NF-kappaB activation can sensitize cells to apoptosis and that inhibition of NF-kappaB 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-kappaB 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-kappaB activity. In androgen-dependent LNCaP cells, Doc and 2ME2 treatment increased the low basal NF-kappaB activity, as determined by Western blot analysis of phospho-IkappaBalpha/p65, NF-kappaB promoter reporter assays, and p65 localization. Treatment of LNCaP cells with parthenolide, a pharmacologic inhibitor of NF-kappaB, or introduction of dominant-negative IkappaBalpha, or an shRNA specific for p65, a component of the NF-kappaB 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-kappaB 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-kappaB, 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-kappaB activity.


CONCLUSIONS
Our data suggest that the combination of antimitotic drugs with NF-kappaB 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-kappaB, will universally enhance cell death in PC cells, notably in the aggressive, castration-resistant variety that does not respond to conventional therapies.
Parrondo
Ricardo
R
Geriatric Research, Education, and Clinical Center and Research Service, Bruce W, Carter Veterans Affairs Medical Center, Miami, FL 33125, USA.
de las Pozas
Alicia
A
Reiner
Teresita
T
Rai
Priyamvada
P
Perez-Stable
Carlos
C
D000077584:2-Methoxyestradiol; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers; D000077143:Docetaxel; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008938:Mitosis / Q000187:drug effects*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053978:Pentacyclic Triterpenes; D011471:Prostatic Neoplasms / Q000473:pathology*; D012717:Sesquiterpenes / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology; D014315:Triterpenes / Q000494:pharmacology; D000094062:Betulinic Acid
D000970:Antineoplastic Agents; D017931:DNA Primers; D016328:NF-kappa B; D053978:Pentacyclic Triterpenes; D012717:Sesquiterpenes; D043823:Taxoids; D014315:Triterpenes; D000077143:Docetaxel; C002669:parthenolide; D004958:Estradiol; D000077584:2-Methoxyestradiol; D000094062:Betulinic Acid