Cisplatin mimics ARF tumor suppressor regulation of RelA (p65) nuclear factor-kappaB transactivation.
The RelA (p65) nuclear factor-kappaB (NF-kappaB) subunit can contribute towards tumor cell survival through inducing the expression of a variety of antiapoptotic genes. However, the NF-kappaB response can show great diversity and is not always antiapoptotic. Here, we find that cisplatin, a DNA cross-linking agent and commonly used anticancer compound, does not affect RelA nuclear translocation but modulates its transcriptional activity. Similar to other genotoxic agents, such as daunorubicin and UV light, cisplatin treatment in the U-2 OS osteosarcoma cell line represses RelA activity and inhibits expression of the NF-kappaB antiapoptotic target gene Bcl-x(L). The mechanism through which cisplatin achieves these effects is different to daunorubicin and UV light but shows great similarity to the RelA regulatory pathway induced by the ARF tumor suppressor: cisplatin regulation of RelA requires ATR/Chk1 activity, represses Bcl-x(L) but not XIAP expression, and results in phosphorylation of RelA at Thr(505). In contrast to these results, another chemotherapeutic drug etoposide activates NF-kappaB and induces expression of these target genes. Thus, within a single tumor cell line, there is great heterogeneity in the NF-kappaB response to different, commonly used chemotherapeutic drugs. These observations suggest that it might be possible to minimize the ability of RelA to inhibit cancer therapy by diagnostically predicting the type of chemotherapeutic drug most compatible with NF-kappaB functionality in a tumor cell type. Moreover, our data indicate that at least with respect to RelA, cisplatin functions as an ARF mimic. Other drugs capable of mimicking this aspect of ARF function might therefore have therapeutic potential.
Campbell
Kirsteen J
KJ
School of Life Sciences, Division of Gene Regulation and Expression, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, United Kingdom.
Witty
James M
JM
Rocha
Sonia
S
Perkins
Neil D
ND
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001859:Bone Neoplasms / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000096:biosynthesis*; D012516:Osteosarcoma / Q000473:pathology; D051996:Transcription Factor RelA / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*; D014466:Ultraviolet Rays
D000970:Antineoplastic Agents; D016328:NF-kappa B; C498143:RELA protein, human; D051996:Transcription Factor RelA; D025803:Tumor Suppressor Protein p14ARF; D002945:Cisplatin