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Prodigiosin-induced cytotoxicity involves RAD51 down-regulation through the JNK and p38 MAPK pathways in human breast

Chien-Hsing Lu1, Shin-Chang Lin, Shu-Yi Yang

  • 1Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.

Toxicology Letters
|May 15, 2012
PubMed

Insights

Prodigiosin, an anticancer pigment, reduces RAD51 protein levels in breast cancer cells, impairing DNA repair and enhancing its own cytotoxicity. This suggests prodigiosin can boost chemotherapy effectiveness by targeting RAD51.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • RAD51 is crucial for DNA double-strand break (DSB) repair via homologous recombination (HR).
  • Elevated RAD51 levels in tumors correlate with chemoresistance.
  • Prodigiosin, a bacterial pigment, exhibits anticancer properties and induces DSBs.

Purpose of the Study:

  • To investigate the role of RAD51 in prodigiosin-induced cytotoxicity.
  • To elucidate the molecular mechanisms underlying prodigiosin's effects on RAD51.

Main Methods:

  • Down-regulation of RAD51 by prodigiosin in human breast carcinoma cell lines.
  • Analysis of RAD51 mRNA expression and proteasomal degradation.
  • Investigating the involvement of JNK and p38 MAPK signaling pathways.
  • Assessing the impact of enforced RAD51 expression on prodigiosin sensitivity.

Main Results:

  • Prodigiosin significantly down-regulates RAD51 expression at the mRNA level.
  • Prodigiosin induces phosphorylation of JNK and p38 MAPK, which mediate RAD51 down-regulation.
  • Inhibition of JNK or p38 MAPK partially reverses prodigiosin-induced RAD51 suppression.
  • Increased RAD51 expression confers resistance to prodigiosin's cytotoxic effects.

Conclusions:

  • RAD51 down-regulation is a key mechanism in prodigiosin's cytotoxic action.
  • Prodigiosin enhances its genotoxicity by suppressing RAD51-mediated HR repair.
  • Prodigiosin may potentiate other DSB-inducing chemotherapeutics by reducing RAD51 levels.

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