Abstract
Bisindolylmaleimides (Bis) were originally described as protein kinase C inhibitors. Several studies have shown that Bis potentiate tumor necrosis factor (TNF) receptor family-mediated apoptosis in lymphoid and dendritic cells, but the inhibition of protein kinase C cannot account for these effects (Zhou, T., Song, L., Yang, P., Wang, Z., Lui, D., and Jope, R. S. (1999) Nat. Med. 5, 42-48). We investigated the effect of four Bis derivatives (I, II, VIII, and IX) in human prostatic carcinoma cell lines and found that Bis IX was the most potent inducer of apoptosis under simultaneous treatment with TNF-alpha, agonistic anti-Fas monoclonal antibody, and TNF-related apoptosis-inducing ligand (TRAIL). Bis IX synergistically induced caspase activity in combination with apoptosis-inducing ligands and converted the phenotype of cell lines from apoptosis-resistant to -sensitive. Bis IX induced p53 accumulation in LNCaP (lymph node carcinoma of prostate), which expresses wild-type p53 that was not accompanied by the induction of p53-responsive genes, p21/WAF1, and Mdm2. Moreover, the induction of p21/WAF1 and Mdm2 by doxorubicin was abrogated by simultaneous treatment with Bis IX. These effects apparently result from general inhibition of transcription by Bis IX. We have shown by Northern blot analysis that the transcription activity of the hygromycin gene after transient transfection of pcDNA3.1-Hygro plasmid in 293 and HeLa cells was inhibited by Bis IX in a dose-dependent manner. Moreover, DNA binding activity of Bis IX was prevented by actinomycin D, suggesting that actinomycin D and Bis IX have similar mechanisms of interaction with DNA. In addition, we found that actinomycin D and Bis IX induced caspase activity to the same extent during TRAIL-mediated apoptosis. In summary, these results suggest that Bis IX potentiates TNF receptor family-mediated cell death in part as an inhibitor of transcription.
Highlights
Zhou et al (4) estimated the potentiating effect of nine Bis derivatives on Fas-mediated apoptosis in astrocytoma 1321N1 cells and found that some Bis derivatives were capable of substantially facilitating Fas-mediated apoptosis in these cells
We investigated the effect of four Bis derivatives (I, II, VIII, and IX) in human prostatic carcinoma cell lines and found that Bis IX was the most potent inducer of apoptosis under simultaneous treatment with tumor necrosis factor (TNF)-␣, agonistic anti-Fas monoclonal antibody, and TNF-related apoptosis-inducing ligand (TRAIL)
We have previously reported that PC3 is sensitive to Fas- and TRAILmediated apoptosis (7), LNCaP is sensitive to TNF-␣ treatment but resistant to Fas- and TRAIL-mediated cell death, and DU145 is resistant to treatment with all three ligands (9, 11)
Summary
Zhou et al (4) estimated the potentiating effect of nine Bis derivatives on Fas-mediated apoptosis in astrocytoma 1321N1 cells and found that some Bis derivatives were capable of substantially facilitating Fas-mediated apoptosis in these cells. The Bis derivatives tested were described as potent inhibitors of PKC, but three other PKC inhibitors structurally unrelated to Bis were tested and were ineffective in potentiating Fas-mediated apoptosis Based on these results, the authors concluded that the inhibition of PKC could not account for the potentiation of Fas-mediated apoptosis by Bis. The authors showed that Bis VIII potentiated TNF-mediated apoptosis in 1321N1 cells and greatly facilitated Fas-mediated apoptosis in several human T cell lines and in activated T cells. We examined the effect of Bis I, II, VIII, and IX in three human prostatic carcinoma cell lines, DU145, LNCaP, and PC3 These experiments showed that Bis IX was the most potent inducer of apoptosis under simultaneous treatment with TNF-␣, agonistic anti-Fas mAb (IPO-4), and TRAIL. Bis IX binds to the mitochondria and inhibits transcription by binding with DNA to the actinomycin D (act D)-related sites These results provide new insight into the mechanisms by which Bis IX potentiates TNF receptor family-mediated apoptosis
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