The rad51-stimulatory compound rs-1 can exploit the rad51 overexpression that exists in cancer cells and tumors

Jennifer M. Mason, Hillary L. Logan, Brian Budke, Megan Wu, Michal Pawlowski, Ralph R. Weichselbaum, Alan P. Kozikowski, Douglas K. Bishop, Philip P. Connell

Research output: Contribution to journalArticlepeer-review

Abstract

RAD51 is the central protein that catalyzes DNA repair via homologous recombination, a process that ensures genomic stability. RAD51 protein is commonly expressed at high levels in cancer cells relative to their noncancerous precursors. High levels of RAD51 expression can lead to the formation of genotoxic RAD51 protein complexes on undamaged chromatin. We developed a therapeutic approach that exploits this potentially toxic feature of malignancy, using compounds that stimulate the DNA-binding activity of RAD51 to promote cancer cell death. A panel of immortalized cell lines was challenged with the RAD51-stimulatory compound RS-1. Resistance to RS-1 tended to occur in cells with higher levels of RAD54L and RAD54B, which are Swi2/Snf2-related translocases known to dissociate RAD51 filaments from dsDNA. In PC3 prostate cancer cells, RS-1-induced lethality was accompanied by the formation of microscopically visibleRAD51 nuclear protein foci occurring in the absence of any DNA-damaging treatment. Treatment with RS-1 promoted significant antitumor responses in a mouse model, providing proof-of-principle for this novel therapeutic strategy.

Original languageEnglish (US)
Pages (from-to)3546-3555
Number of pages10
JournalCancer Research
Volume74
Issue number13
DOIs
StatePublished - Jul 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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