DNA adducts of decarbamoyl mitomycin C efficiently kill cells without wild-type p53 resulting from proteasome-mediated degradation of checkpoint protein 1.

Published

Journal Article

The mitomycin derivative 10-decarbamoyl mitomycin C (DMC) more rapidly activates a p53-independent cell death pathway than mitomycin C (MC). We recently documented that an increased proportion of mitosene1-beta-adduct formation occurs in human cells treated with DMC in comparison to those treated with MC. Here, we compare the cellular and molecular response of human cancer cells treated with MC and DMC. We find the increase in mitosene 1-beta-adduct formation correlates with a condensed nuclear morphology and increased cytotoxicity in human cancer cells with or without p53. DMC caused more DNA damage than MC in the nuclear and mitochondrial genomes. Checkpoint 1 protein (Chk1) was depleted following DMC, and the depletion of Chk1 by DMC was achieved through the ubiquitin proteasome pathway since chemical inhibition of the proteasome protected against Chk1 depletion. Gene silencing of Chk1 by siRNA increased the cytotoxicity of MC. DMC treatment caused a decrease in the level of total ubiquitinated proteins without increasing proteasome activity, suggesting that DMC mediated DNA adducts facilitate signal transduction to a pathway targeting cellular proteins for proteolysis. Thus, the mitosene-1-beta stereoisomeric DNA adducts produced by the DMC signal for a p53-independent mode of cell death correlated with reduced nuclear size, persistent DNA damage, increased ubiquitin proteolysis and reduced Chk1 protein.

Full Text

Duke Authors

Cited Authors

  • Boamah, EK; Brekman, A; Tomasz, M; Myeku, N; Figueiredo-Pereira, M; Hunter, S; Meyer, J; Bhosle, RC; Bargonetti, J

Published Date

  • July 2010

Published In

Volume / Issue

  • 23 / 7

Start / End Page

  • 1151 - 1162

PubMed ID

  • 20536192

Pubmed Central ID

  • 20536192

Electronic International Standard Serial Number (EISSN)

  • 1520-5010

International Standard Serial Number (ISSN)

  • 0893-228X

Digital Object Identifier (DOI)

  • 10.1021/tx900420k

Language

  • eng