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

Noa Rabinowicz1,2, Lingegowda S Mangala3,4, Kevin R Brown5

  • 1Cancer Research Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.

Oncotarget
|April 21, 2017
PubMed

Insights

Scientists found that targeting the STIL gene can effectively treat advanced ovarian cancer. Inhibiting STIL enhances chemotherapy, offering a promising new therapeutic strategy for this incurable disease.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Advanced ovarian cancer remains incurable, necessitating the development of novel therapeutic strategies.
  • Identifying new molecular targets is crucial for improving treatment outcomes in ovarian cancer.

Purpose of the Study:

  • To identify novel therapeutic targets for advanced ovarian cancer.
  • To investigate the role of the centriolar replication factor STIL in ovarian cancer progression and treatment.

Main Methods:

  • Conducted a large-scale shRNA screen across 42 ovarian cancer cell lines to identify essential genes.
  • Validated findings in vivo using orthotopic human ovarian cancer mouse models.
  • Utilized siRNA delivered via neutral liposomes for STIL depletion and assessed anti-tumor effects, alone and in combination with cisplatin.

Main Results:

  • STIL was identified as an essential gene for ovarian cancer cell survival and proliferation.
  • STIL depletion via siRNA demonstrated significant anti-tumor effects in vivo, enhanced by cisplatin combination therapy.
  • STIL inhibition led to increased DNA double-strand breaks, genomic instability, and micronuclei formation.
  • Notably, STIL depletion enhanced homologous recombination repair and increased BRCA1 and RAD51 foci in response to DNA damage.

Conclusions:

  • STIL is a critical therapeutic target for ovarian cancer.
  • Inhibition of STIL significantly potentiates the efficacy of DNA-damaging chemotherapeutic drugs.
  • Targeting STIL represents a promising strategy to enhance ovarian cancer treatment outcomes.
Keywords:
DNA damageSTILcentrosomesgenomic instabilityovarian cancer

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