Targeting the centriolar replication factor STIL synergizes with DNA damaging agents for treatment of ovarian cancer
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Noa Rabinowicz1,2, Lingegowda S. Mangala3,4, Kevin R. Brown5, Cintia Checa-Rodriguez6, Asher Castiel1,2, Oren Moskovich1,2, Giulia Zarfati1, Luba Trakhtenbrot1, Adva Levy-Barda1, Dahai Jiang3,4, Cristian Rodriguez-Aguayo4,7, Sunila Pradeep3, Yael van Praag1, Gabriel Lopez-Berestein4,7, Ahuvit David1,2, Ilya Novikov9, Pablo Huertas6, Robert Rottapel10, Anil K. Sood3,4,8, Shai Izraeli1,2,11
1Cancer Research Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
2Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
3Department of Gynecologic Oncology, MD Anderson Cancer Center, Houston, Texas, USA
4Center for RNA Interference and Non-Coding RNA, MD Anderson Cancer Center, Houston, Texas, USA
5Donnelly Centre and The Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada
6Department of Genetics, University of Sevilla and Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Sevilla, Spain
7Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, Texas, USA
8Department of Cancer Biology, MD Anderson Cancer Center, Houston, Texas, USA
9Biostatistical Unit, Gertner Institute for Epidemiology and Health Policy Research, Ramat Gan, Israel
10Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada
11The Gene Development and Environment Pediatric Research Institute, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
Shai Izraeli, email: firstname.lastname@example.org
Keywords: STIL, centrosomes, ovarian cancer, DNA damage, genomic instability
Received: August 11, 2016 Accepted: February 20, 2017 Published: March 10, 2017
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.
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