Abstract
Abstract Purpose This study aims to interrogate if basonuclin1 (BNC1), a key gene identified through integrative TCGA-based functional genomic analysis, is a relevant target for overcoming chemo-resistance in high-grade serous ovarian cancer (HGS-OvCa). BNC1 is a transcription factor which can regulate ribosomal biogenesis and cell proliferation. Methods TCGA mRNA expression and clinical response data were used to systematically identify genes associated with chemo-resistance in patients with HGS-OvCa. Gene-specific effects were subsequently studied for selected targets in vitro. BNC1 targeted siRNA was used to study the functional role of BNC1 in chemo-resistance. Apoptosis and cell cycle analyses were carried out following BNC1 silencing in ovarian cancer cell lines with or without the presence of cisplatin. The in vivo effects of silencing BNC1 on the chemosensitivity were tested using an orthotopic mouse model (A2780CP20) of ovarian cancer. Results The expression of BNC1 was found to be increased by more than two-fold (Agilent platform; p<0.001) in chemo-resistant tumors in the TCGA dataset. A 5-fold increase in its expression level was also observed in cisplatin-resistant A2780-CP20 and IGROV-CP20 cells compared to parental cell lines. BNC1 silencing increased the sensitivity of A2780CP20 cells to cisplatin treatment (IC50) with a 30% increase in the percentage of apoptotic cells present at 72 hours following cisplatin treatment, when compared to cells treated with control siRNA. Profound G2-cell cycle arrest was also noted following combined siBNC1 and cisplatin (IC30) treatment (68% vs. 28%; siBNC1 plus cisplatin vs. siControl plus cisplatin; p<0.0001). Importantly, combinational treatment of siBNC1 and cisplatin resulted in a 90% reduction in tumor burden in chemo-resistant A2780CP20 orthotopic mouse model when compared to control siRNA plus cisplatin treatment group (p<0.01). Conclusion Collectively, BNC1 represents an important target for enhancing chemosensitivity in ovarian tumors and its down-regulation could lead to better clinical outcome. Citation Format: Sherry Y. Wu, Anna K. Unruh, Rajesha Rupaimoole, Cristina Ivan, Dennis Ruder, Sunila Pradeep, Vasudha Sehgal, Cristian Rodriguez-Aguayo, Chad Pecot, Takahito Miyake, Gabriel Lopez-Berestein, Prahlad Ram, Keith A. Baggerly, Anil K. Sood. Overcoming platinum-resistance in ovarian cancer via targeting basonuclin1 (BNC1). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2036. doi:10.1158/1538-7445.AM2013-2036
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