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p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-gamma

R D Meng1, W S El-Deiry

  • 1Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Philadelphia, Pennsylvania, 19104, USA.

Experimental Cell Research
|January 5, 2001
PubMed

Insights

Certain drugs and cytokines can induce KILLER/DR5 mRNA expression independently of p53, suggesting a role in apoptosis for tumors lacking wild-type p53. This highlights KILLER/DR5 as a potential chemotherapy target.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Death Pathways

Background:

  • KILLER/DR5 is a proapoptotic receptor that binds TRAIL.
  • Previous studies indicated p53-dependent KILLER/DR5 mRNA induction after DNA damage.
  • Some apoptosis-inducing drugs upregulate KILLER/DR5 mRNA in p53-mutated cells.

Purpose of the Study:

  • To investigate the p53-independent induction of KILLER/DR5 mRNA by various apoptosis-inducing agents.
  • To identify specific drugs and signaling pathways that modulate KILLER/DR5 expression in a p53-independent manner.
  • To explore the therapeutic potential of targeting KILLER/DR5 in p53-deficient cancers.

Main Methods:

  • Treatment of cancer cell lines (colon, melanoma, glioblastoma) with various apoptosis-inducing drugs (beta-lapachone, betulinic acid, dexamethasone, prednisolone) and cytokines (IFN-gamma, TNF-alpha).
  • Analysis of KILLER/DR5 mRNA expression levels.
  • Assessment of p53 status (wild-type vs. mutant).
  • Inhibition studies using actinomycin D and evaluation of STAT1 status.

Main Results:

  • Beta-lapachone increased KILLER/DR5 mRNA in wild-type p53 colon cancer cells but not in mutant p53 cells.
  • Betulinic acid induced apoptosis and KILLER/DR5 mRNA in a p53-independent manner in melanoma and glioblastoma.
  • Dexamethasone elevated KILLER/DR5 mRNA in p53-mutated cancer cells, an effect inhibited by actinomycin D.
  • IFN-gamma and TNF-alpha induced apoptosis and KILLER/DR5 mRNA in p53-mutated cells, with delayed induction in STAT1-deficient cells.

Conclusions:

  • Specific drugs and cytokines can induce KILLER/DR5 mRNA expression through p53-independent pathways.
  • KILLER/DR5 may serve as a therapeutic target for cancers with mutated or absent p53.
  • Further research is warranted to elucidate the mechanisms and therapeutic applications of p53-independent KILLER/DR5 induction.

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