title: Knockdown of clusterin expression increases the in vitro sensitivity of human prostate cancer cells to paclitaxel.
abstract: Clusterin/apolipoprotein J is a secreted heterodimeric glycoprotein that is implicated in several pathophysiological processes, including tissue remodeling, reproduction, lipid transport, and apoptosis. Although previous studies demonstrated that clusterin is able to protect against apoptosis, the role of the clusterin in cellular proliferation remains elusive. To determine whether clusterin plays an important role in cellular proliferation, the function of clusterin was examined using a small interfering RNA (siRNA) in PC3 human prostate cancer cells. Transient transfection with clusterin siRNA resulted in significant suppression of clusterin mRNA and protein expression. Clusterin knockdown resulted in a decrease in protein expression of phospho-Akt and an increase in expression of proteins phosphatase type 2AC (PP2AC) and phosphorylation of p38. However, treatment with PP2AC siRNA exerted minimal effects on clusterin expression. Interestingly, clusterin mRNA expression was reduced in paclitaxel-treated cells, and the cytotoxic effect of paclitaxel was more potent when cells were incubated with clusterin siRNA. In addition, co-treatment with paclitaxel and clusterin siRNA significantly enhanced PP2AC levels. Taken together, these results indicate that clusterin plays a crucial role in PC3 cell proliferation and that clusterin depletion may contribute to enhanced sensitivity of PC3 cells to anticancer agents such as paclitaxel.
authors.affiliation: a College of Pharmacy , Chung-Ang University , Seoul , Korea.
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Chun
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D051152:Clusterin / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D017239:Paclitaxel / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D051152:Clusterin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017239:Paclitaxel