Targeting the centriolar replication factor STIL synergizes with DNA damaging agents for treatment of ovarian cancer

Noa Rabinowicz, Lingegowda S. Mangala, Kevin R. Brown, Cintia Checa-Rodriguez, Asher Castiel, Oren Moskovich, Giulia Zarfati, Luba Trakhtenbrot, Adva Levy-Barda, Dahai Jiang, Cristian Rodriguez-Aguayo, Sunila Pradeep, Yael van Praag, Gabriel Lopez-Berestein, Ahuvit David, Ilya Novikov, Pablo Huertas, Robert Rottapel, Anil K. Sood, Shai Izraeli

Research output: Contribution to journalArticlepeer-review

Abstract

Advanced ovarian cancer is an incurable disease. Thus, novel therapies are required. We wished to identify new therapeutic targets for ovarian cancer. ShRNA screen performed in 42 ovarian cancer cell lines identified the centriolar replication factor STIL as an essential gene for ovarian cancer cells. This was verified in-vivo in orthotopic human ovarian cancer mouse models. STIL depletion by administration of siRNA in neutral liposomes resulted in robust anti-tumor effect that was further enhanced in combination with cisplatin. Consistent with this finding, STIL depletion enhanced the extent of DNA double strand breaks caused by DNA damaging agents. This was associated with centrosomal depletion, ongoing genomic instability and enhanced formation of micronuclei. Interestingly, the ongoing DNA damage was not associated with reduced DNA repair. Indeed, we observed that depletion of STIL enhanced canonical homologous recombination repair and increased BRCA1 and RAD51 foci in response to DNA double strand breaks. Thus, inhibition of STIL significantly enhances the efficacy of DNA damaging chemotherapeutic drugs in treatment of ovarian cancer.

Original languageEnglish
Pages (from-to)27380-27392
Number of pages13
JournalOncotarget
Volume8
Issue number16
DOIs
StatePublished - 2017

Keywords

  • Centrosomes
  • DNA damage
  • Genomic instability
  • Ovarian cancer
  • STIL

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