TY - JOUR
T1 - Targeting the centriolar replication factor STIL synergizes with DNA damaging agents for treatment of ovarian cancer
AU - Rabinowicz, Noa
AU - Mangala, Lingegowda S.
AU - Brown, Kevin R.
AU - Checa-Rodriguez, Cintia
AU - Castiel, Asher
AU - Moskovich, Oren
AU - Zarfati, Giulia
AU - Trakhtenbrot, Luba
AU - Levy-Barda, Adva
AU - Jiang, Dahai
AU - Rodriguez-Aguayo, Cristian
AU - Pradeep, Sunila
AU - van Praag, Yael
AU - Lopez-Berestein, Gabriel
AU - David, Ahuvit
AU - Novikov, Ilya
AU - Huertas, Pablo
AU - Rottapel, Robert
AU - Sood, Anil K.
AU - Izraeli, Shai
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Centrosomes
KW - DNA damage
KW - Genomic instability
KW - Ovarian cancer
KW - STIL
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UR - http://www.scopus.com/inward/citedby.url?scp=85017503134&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.16068
DO - 10.18632/oncotarget.16068
M3 - Article
C2 - 28423708
AN - SCOPUS:85017503134
SN - 1949-2553
VL - 8
SP - 27380
EP - 27392
JO - Oncotarget
JF - Oncotarget
IS - 16
ER -