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Geldanamycin promotes premature mitotic entry and micronucleation in irradiated p53/p21 deficient colon carcinoma

D M Moran1, G Gawlak, M S Jayaprakash

  • 1Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.

Oncogene
|May 28, 2008
PubMed

Insights

Heat-shock protein 90 (HSP90) inhibition with geldanamycin abrogates radiation-induced G(2) arrest in p53-compromised cancer cells, enhancing cell death. This suggests combination therapy for p53-mutant cancers.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Ionizing radiation (IR) induces a G(2)-phase cell-cycle arrest in both wild-type and p53-null/mutant cells.
  • Heat-shock protein 90 (HSP90) plays a role in cellular stress responses and protein stability.

Purpose of the Study:

  • To investigate the effect of the HSP90 inhibitor geldanamycin (GA) on IR-induced G(2) arrest in human colon adenocarcinoma cells with varying p53 statuses.
  • To explore the potential of HSP90 inhibition as a therapeutic strategy to enhance IR efficacy in p53-compromised cancers.

Main Methods:

  • Treatment of human colon adenocarcinoma cells (wild-type, null, or mutant for p53) with ionizing radiation (IR) and/or geldanamycin (GA).
  • Analysis of cell-cycle progression, mitotic figures, gammaH2AX expression, micronucleation, and levels of key cell-cycle regulatory proteins (Wee1, Chk1, Cdc2, p21).
  • Clonogenic survival assays to assess cell sensitivity to GA and IR treatments.

Main Results:

  • Geldanamycin (GA) abrogated IR-induced G(2) arrest in p53-null/mutant cells, leading to premature mitosis with aberrant features.
  • Wild-type p53 cells were resistant to GA-induced G(2) checkpoint abrogation.
  • GA decreased Wee1, Chk1, and inhibitory Cdc2 phosphorylation independently of p53 status, with p21 identified as a key mediator of p53-dependent resistance.
  • p53 and p21-null cells showed increased sensitivity to GA alone or in combination with IR.

Conclusions:

  • HSP90 inhibition by GA can overcome IR-induced G(2) arrest in p53-compromised cancer cells, potentially by affecting Wee1, Chk1, and Cdc2.
  • p21 acts as a downstream effector of p53 in mediating resistance to G(2) checkpoint abrogation.
  • Combination therapy of IR with HSP90 inhibitors shows promise for treating cancers lacking wild-type p53, due to enhanced radiosensitivity.

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