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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 

Tumor necrosis factor-alpha-induced apoptosis in prostate cancer cells through inhibition of nuclear factor-kappaB by an IkappaBalpha "super-repressor".

Prostate cancer patients experiencing a relapse in disease often express high serum tumor necrosis factor-alpha (TNF-alpha) levels. Many androgen-insensitive prostate cancer cells are TNF-alpha insensitive because of the expression of antiapoptotic genes as part of the nuclear factor-kappaB (NF-kappaB) family of transcription factors. NF-kappaB stimulates gene transcription when expressed in the nucleus; however, in resting cells, this nuclear import is prevented by association with the cytoplasmic inhibitor IkappaBalpha. This cytoplasmic retention of NF-kappaB is uncoupled by many extracellular signals including low levels of TNF-alpha. During normal cell activation, nuclear translocation of NF-kappaB is preceded by phosphorylation and degradation of IkappaBalpha. When phosphorylation is blocked, IkappaBalpha remains intact, thereby blocking NF-kappaB translocation to the nucleus and subsequent activation of antiapoptotic genes that cause TNF-alpha insensitivity. We tested whether a "super-repressor" of NF-kappaB activity could be transfected into prostate cancer cells and make them TNF-alpha sensitive. PC-3 and LNCaP cells were stimulated with TNF-alpha (10 ng/ml) for 24 h in the presence or absence of the IkappaBalpha "super-repressor" (p6R-IkappaB(S32A + S36A)). NF-kappaB activity was measured by electrophoretic mobility shift assay and the steady state levels of the cytoplasmic IkappaBalpha protein were measured by Western blot. Secretory IL-6 and IL-6 mRNA were measured by ELISA. p6R-IkappaB(S32A + S36A) blocked the stimulation of NF-kappaB activity by TNF-alpha in prostate cancer cells. It also subsequently decreased IL-6 production by TNF-alpha. We conclude that these data demonstrate that inhibition of NF-kappaB selectively sensitizes previously insensitive prostate cancer cells to TNF-alpha.[1]

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