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Cisplatin mimics ARF tumor suppressor regulation of RelA (p65) nuclear factor-kappaB transactivation

Kirsteen J Campbell1, James M Witty, Sonia Rocha

  • 1School of Life Sciences, Division of Gene Regulation and Expression, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, United Kingdom.

Cancer Research
|January 21, 2006
PubMed

Insights

Cisplatin, an anticancer drug, represses the activity of the RelA (p65) nuclear factor-kappaB (NF-kappaB) subunit, inhibiting tumor cell survival genes. This suggests personalized cancer therapy based on NF-kappaB drug compatibility.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • The RelA (p65) nuclear factor-kappaB (NF-kappaB) subunit typically promotes tumor cell survival by upregulating antiapoptotic genes.
  • However, the NF-kappaB pathway exhibits diverse responses and is not consistently antiapoptotic.

Purpose of the Study:

  • To investigate the effect of cisplatin on RelA/NF-kappaB transcriptional activity in osteosarcoma cells.
  • To elucidate the mechanism of cisplatin-induced RelA modulation and compare it with other genotoxic agents and chemotherapeutics.

Main Methods:

  • Treatment of U-2 OS osteosarcoma cells with cisplatin.
  • Analysis of RelA nuclear translocation and transcriptional activity.
  • Assessment of NF-kappaB target gene expression (Bcl-x(L), XIAP).
  • Investigation of the role of ATR/Chk1 pathway and RelA phosphorylation at Thr(505).

Main Results:

  • Cisplatin modulates RelA transcriptional activity without affecting nuclear translocation.
  • Cisplatin represses RelA activity and inhibits Bcl-x(L) expression, similar to daunorubicin and UV light but via a distinct mechanism.
  • Cisplatin-induced RelA regulation requires ATR/Chk1, represses Bcl-x(L) (not XIAP), and involves RelA phosphorylation at Thr(505), mimicking ARF suppressor function.
  • Etoposide, another chemotherapeutic, activates NF-kappaB and induces target gene expression.
  • Significant heterogeneity exists in NF-kappaB response to different chemotherapeutics within the same cell line.

Conclusions:

  • Cisplatin acts as an ARF mimic by inhibiting RelA transcriptional activity.
  • The differential response of NF-kappaB to various chemotherapeutics highlights the potential for personalized cancer treatment strategies.
  • Identifying drugs compatible with specific NF-kappaB functionality in tumor cells could overcome therapy resistance.

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