title: Notch3-specific inhibition using siRNA knockdown or GSI sensitizes paclitaxel-resistant ovarian cancer cells.
abstract: Notch signaling plays an important role in ovarian cancer chemoresistance, which is responsible for recurrence. Gamma-secretase inhibitor (GSI) is a broad-spectrum Notch inhibitor, but it has serious side effects. The efficacy of Notch3-specific inhibition in paclitaxel-resistant ovarian cancers was assessed in this study, which has not yet been evaluated relative to GSI. To analyze the effect of Notch3-specific inhibition on paclitaxel-resistant ovarian cancers, we compared cell viability, apoptosis, cell migration, angiogenesis, cell cycle, and spheroid formation after treatment with either Notch3 siRNA or GSI in paclitaxel-resistant SKpac cells and parental SKOV3 cells. Expression levels of survival, cell cycle, and apoptosis-related proteins were measured and compared between groups. Notch3 was significantly overexpressed in chemoresistant cancer tissues and cell lines relative to chemosensitive group. In paclitaxel-resistant cancer cells, Notch inhibition significantly reduced viability, migration, and angiogenesis and increased apoptosis, thereby boosting sensitivity to paclitaxel. Spheroid formation was also significantly reduced. Both Notch3 siRNA-treated cells and GSI-treated cells arrested in the G2/M phase of the cell cycle. Proteins of cell survival, cyclin D1 and cyclin D3 were reduced, whereas p21 and p27 were elevated. Both GSI and Notch3 siRNA treatment reduced expression of anti-apoptotic proteins (BCL-W, BCL2, and BCL-XL) and increased expression of pro-apoptotic proteins (Bad, Bak, Bim, Bid, and Bax). These results indicate that Notch3-specific inhibition sensitizes paclitaxel-resistant cancer cells to paclitaxel treatment, with an efficacy comparable to that of GSI. This approach would be likely to avoid the side effects of broad-spectrum GSI treatment. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.|Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.
authors.forename: Haeyoun
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.
authors.forename: Ju-Yeon
authors.initials: JY
authors.lastname: Jeong
authors.affiliation: Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.
authors.forename: Ji-Ye
authors.initials: JY
authors.lastname: Song
authors.affiliation: Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.|Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.
authors.forename: Tae Heon
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.|Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.
authors.forename: Gwangil
authors.initials: G
authors.lastname: Kim
authors.affiliation: Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.
authors.forename: Jin Hyung
authors.initials: JH
authors.lastname: Huh
authors.affiliation: Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.
authors.forename: Ah-Young
authors.initials: AY
authors.lastname: Kwon
authors.affiliation: Department of Gynecologic Oncology, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.
authors.forename: Sang Geun
authors.initials: SG
authors.lastname: Jung
authors.affiliation: Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.|Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: An
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000628:therapy*; D017239:Paclitaxel / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology*; D000071656:Receptor, Notch3 / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: C499374:NOTCH3 protein, human; D009842:Oligopeptides; D034741:RNA, Small Interfering; D000071656:Receptor, Notch3; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; D017239:Paclitaxel
keywords: GSI; Notch signaling; Notch3 siRNA; ovarian cancer; paclitaxel-resistance