title: Role of Wnt/β-catenin, Wnt/c-Jun N-terminal kinase and Wnt/Ca2+pathways in cisplatin-induced chemoresistance in ovarian cancer.
abstract: The aim of the present study was to explore the expression of Wnt signaling proteins β-catenin, c-Jun N-terminal kinase (JNK) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in ovarian cancer cells, and assess the correlation between this expression and cisplatin-induced chemoresistance. SKOV3 ovarian carcinoma cells and SKOV3/DDP (cisplatin resistant) cells were treated with cisplatin in the absence or presence of a Wnt signaling activator (CHIR-99021, glycogen synthase kinase 3β inhibitor) or inhibitor (XAV-939, tankyrase inhibitor). Following incubation for 48 h, cell viability, proliferation and cytotoxicity were measured using a sensitive colorimetric cell counting kit. Expression levels of β-catenin, JNK and CaMKII were detected by western blot and immunofluorescence staining. The results of the current study identified that β-catenin and JNK expression levels were significantly higher (P<0.01 and P<0.05 respectively), while CaMKII expression was lower (P>0.05), in SKOV3/DDP cells compared with SKOV3 cells. Moreover, following treatment with 20 µM cisplatin, reduced expression of β-catenin and JNK (P<0.05 and P<0.01 respectively), and increased expression of CaMKII (P<0.01), was observed in SKOV3 and SKOV3/DPP cell lines. Furthermore, inhibition of β-catenin signaling by XAV-939 effectively reversed cisplatin chemoresistance in SKOV3/DDP cells. Similarly, XAV-939 downregulated JNK expression (P<0.001), but upregulated CaMKII expression (P<0.001), in SKOV3/DDP cells. In conclusion, abnormal activation of Wnt/β-catenin and Wnt/JNK signaling pathways in ovarian cancer cells promotes cisplatin resistance, while the Wnt/Ca2+signaling pathway reduces cisplatin resistance. This indicates that β-catenin, JNK and CaMKII are potential therapeutic targets in chemoresistant ovarian cancers.
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Lu
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Shujun
authors.initials: S
authors.lastname: Feng
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Sainan
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Qiu
authors.affiliation: Department of Computing, Brain Cognition Computing Lab, University of Kent, Kent CT2 7NZ, UK.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zheng
keywords: Ca2+/calmodulin-dependent protein kinase II; c-Jun N-terminal kinase; cisplatin chemoresistance; ovarian cancer; β-catenin