Abstract:
:Development of chemoresistance in androgen-refractory prostate cancer cells is partly due to constitutive activation of Rel/NF-kappaB transcription factors that regulate several cell survival and anti-apoptotic genes. In this study we examined whether betulinic acid (BetA), a pentacyclic triterpene from the bark of white birch, is effective in inhibiting NF-kappaB expression in androgen-refractory human prostate cancer cells exhibiting high constitutive NF-kappaB expression. Treatment of PC-3 cells with BetA inhibited DNA binding and reduced nuclear levels of the NF-kappaB/p65. BetA-mediated NF-kappaB inhibition involved decreased IKK activity and phosphorylation of IkappaBalpha at serine 32/36 followed by its degradation. Reporter assays revealed that NF-kappaB inhibition by BetA is transcriptionally active. These effects were found to correlate with a shift in Bax/Bcl-2 ratio and cleavage of poly(ADP)ribose polymerase more towards apoptosis. BetA also inhibited TNFalpha-induced activation of NF-kappaB via the IkappaBalpha pathway, thereby sensitizing the cells to TNFalpha-induced apoptosis. Our studies demonstrate that BetA effectively inhibits constitutive NF-kappaB activation and supports the rationale for targeting NF-kappaB through combination protocols with BetA in androgen-refractory prostate cancer.
journal_name
Mol Carcinogjournal_title
Molecular carcinogenesisauthors
Rabi T,Shukla S,Gupta Sdoi
10.1002/mc.20447subject
Has Abstractpub_date
2008-12-01 00:00:00pages
964-73issue
12eissn
0899-1987issn
1098-2744journal_volume
47pub_type
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