title: Clusterin silencing sensitizes pancreatic cancer MIA-PaCa-2 cells to gmcitabine via regulation of NF-kB/Bcl-2 signaling.
abstract: Clusterin (CLU) is known as a multifunctional protein involved in a variety of physiological processes including lipid transport, epithelial cell differentiation, tumorigenesis, and apoptosis. Our recent study has demonstrated that knockdown of clusterin sensitizes pancreatic cancer cell lines to gmcitabine treatment. However the details of this survival mechanism remain undefined. Of the various downstream targets of CLU, we examined activation of the NF-kB transcription factor and subsequent transcriptional regulation of BCL-2 gene in pancreatic cancer cell MIA-PaCa-2. The MIA-PaCa-2 cells were transfected with an antisense oligonucleotide (ASO) against clusterin, which led to a decreased protein level of the antiapoptotic gene BCL-2. Furthermore, inhibition of CLU decreased the function of NF-kB, which is capable of transcriptional regulation of the BCL-2 gene. Inhibiting this pathway increased the apoptotic effect of gmcitabine chemotherapy. Re-activated NF-kB resulted in attenuation of ASO-induced effects, followed by the bcl-2 upregulation, and bcl-2 re-inhibition resulted in attenuation of Re-activated NF-kB -induced effects. Animals injected with ASO CLU in MIA-PaCa-2 cells combined with gmcitabine treatment had fewer tumors than gmcitabine or ASO CLU alone. These findings suggest that knockdown of CLU sensitized MIA-PaCa-2 cells to gmcitabine chemotherapy through modulating NF-Kb/bcl-2 pathway.
authors.affiliation: Department of Clinical Lab, People's Hospital of Weifang Weifang, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Clinical Lab, People's Hospital of Laiwu Laiwu, China.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Orthopedics, People's Hospital of Zhangqiu Jinan, China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Clinical Lab, People's Hospital of Zhangqiu Jinan, China.
authors.forename: Chunqing
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Clinical Lab, People's Hospital of Weifang Weifang, China ; Department of General Surgery, The Eighth People's Hospital of Qingdao Qingdao, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Clinical Lab, People's Hospital of Weifang Weifang, China.
authors.forename: Shirong
authors.initials: S
authors.lastname: Li
keywords: NF-kB; Pancreatic cancer; chemotherapy; clusterin