Proteasome inhibitors induce apoptosis of prostate cancer cells by inducing nuclear translocation of IkappaBalpha.
Proteasome inhibitors are known to suppress the proteasome-mediated degradation of IkappaBalpha in stimulated cells. This results in the cytoplasmic retention of NFkappaB and its reduced nuclear transcriptional activity. In this study, we show that in the metastatic prostate cancer cells, the proteasome inhibitors exhibit a novel, previously unrecognized effect: they increase the cellular levels of IkappaBalpha, which then translocates to the nucleus, associates with the nuclear p65 NFkappaB, thus inhibiting the constitutive NFkappaB DNA binding activity and inducing apoptosis. The proteasome inhibition-induced nuclear translocation of IkappaBalpha is dependent on de novo protein synthesis, occurs also in other cell types, and does not require IkappaBalpha phosphorylation on Ser-32. Since NFkappaB activity is constitutively increased in many human cancers as well as in inflammatory disorders, the proteasome inhibition-induced nuclear translocation of IkappaBalpha could thus provide a new therapeutic strategy aimed at the specific inhibition of NFkappaB activity by the nuclear IkappaBalpha.
Vu
Hai-Yen
HY
Department of Biological Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
Juvekar
Ashish
A
Ghosh
Chandra
C
Ramaswami
Sitharam
S
Le
Dung Hong
DH
Vancurova
Ivana
I
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021381:Protein Transport
D015853:Cysteine Proteinase Inhibitors; D020672:I-kappa B Proteins; D007976:Leupeptins; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde