TY - JOUR
T1 - Silencing survivin splice variant 2B leads to antitumor activity in taxane-resistant ovarian cancer
AU - Vivas-Mejia, Pablo E.
AU - Rodriguez-Aguayo, Cristian
AU - Han, Hee Dong
AU - Shahzad, Mian M.K.
AU - Valiyeva, Fatma
AU - Shibayama, Mineko
AU - Chavez-Reyes, Arturo
AU - Sood, Anil K.
AU - Lopez-Berestein, Gabriel
PY - 2011/6/1
Y1 - 2011/6/1
N2 - Purpose: To study the role of survivin and its splice variants in taxane-resistant ovarian cancer. Experimental Design: We assessed the mRNA levels of survivin splice variants in ovarian cancer cell lines and ovarian tumor samples. siRNAs targeting survivin were designed to silence all survivin splice variants (T-siRNA) or survivin 2B (2B-siRNA) in vitro and orthotopic murine models of ovarian cancer. The mechanism of cell death was studied in taxane-resistant ovarian cancer cells and in tumor sections obtained from different mouse tumors. Results: Taxane-resistant ovarian cancer cells express higher survivin mRNA levels than their taxane-sensitive counterparts. Survivin 2B expression was significantly higher in taxane-resistant compared with -sensitive cells. Silencing survivin 2B induced growth inhibitory effects similar to silencing total survivin in vitro. In addition, survivin 2B-siRNA incorporated into DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) nanoliposomes resulted in significant reduction in tumor growth (P < 0.05) in orthotopic murine models of ovarian cancer, and these effects were similar to T-siRNA-DOPC. The antitumor effects were further enhanced in combination with docetaxel chemotherapy (P < 0.01). Finally, we found a significant association between survivin 2B expression and progression-free survival in 117 epithelial ovarian cancers obtained at primary debulking surgery. Conclusions: These data identify survivin 2B as an important target in ovarian cancer and provide a translational path forward for developing new therapies against this target.
AB - Purpose: To study the role of survivin and its splice variants in taxane-resistant ovarian cancer. Experimental Design: We assessed the mRNA levels of survivin splice variants in ovarian cancer cell lines and ovarian tumor samples. siRNAs targeting survivin were designed to silence all survivin splice variants (T-siRNA) or survivin 2B (2B-siRNA) in vitro and orthotopic murine models of ovarian cancer. The mechanism of cell death was studied in taxane-resistant ovarian cancer cells and in tumor sections obtained from different mouse tumors. Results: Taxane-resistant ovarian cancer cells express higher survivin mRNA levels than their taxane-sensitive counterparts. Survivin 2B expression was significantly higher in taxane-resistant compared with -sensitive cells. Silencing survivin 2B induced growth inhibitory effects similar to silencing total survivin in vitro. In addition, survivin 2B-siRNA incorporated into DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) nanoliposomes resulted in significant reduction in tumor growth (P < 0.05) in orthotopic murine models of ovarian cancer, and these effects were similar to T-siRNA-DOPC. The antitumor effects were further enhanced in combination with docetaxel chemotherapy (P < 0.01). Finally, we found a significant association between survivin 2B expression and progression-free survival in 117 epithelial ovarian cancers obtained at primary debulking surgery. Conclusions: These data identify survivin 2B as an important target in ovarian cancer and provide a translational path forward for developing new therapies against this target.
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U2 - 10.1158/1078-0432.CCR-11-0233
DO - 10.1158/1078-0432.CCR-11-0233
M3 - Article
C2 - 21512144
AN - SCOPUS:79957927217
SN - 1078-0432
VL - 17
SP - 3716
EP - 3726
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 11
ER -