title: Secretory clusterin contributes to oxaliplatin resistance by activating Akt pathway in hepatocellular carcinoma.
abstract: Secretory clusterin (sCLU) is expressed in numerous cancers and is associated with the resistance to chemotherapy. However, the role of sCLU in the resistance of hepatocellular carcinoma (HCC) to oxaliplatin (OXA), a recently used third-generation platinum agent, remains unclear. The stable transfectants that are depleted of or overexpress sCLU and OXA-resistant cells were generated using human HCC cells. Overexpression of sCLU abrogated OXA-induced inhibition of cell growth and cell apoptosis, but depletion of sCLU synergized with OXA to inhibit cell growth and enhance cell apoptosis, by regulating proteins involved in mitochondrial apoptosis pathways, such as Bcl-2, Bax, Bcl-xL and caspase-9, and affecting phosphorylation of Akt and GSK-3β. Overexpression of sCLU in either OXA-resistant cells or stable transfectants that overexpress sCLU significantly increased phosphorylated Akt. However, specific inhibition of Akt enhanced sensitivity of sCLU-overexpressing cells to OXA, but had no effect on sCLU expression, suggesting that the regulatory effects between sCLU and pAkt may be in a one-way manner in HCC cells. The expression levels of sCLU affected the therapeutic efficacy of OXA to treat HCC tumors established in immunodeficiency mice. The results have demonstrated that sCLU contributes to OXA resistance by activating Akt pathway, indicating that sCLU may be a novel molecular target for overcoming OXA resistance in HCC.
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xiu
authors.forename: Xuesong
authors.initials: X
authors.lastname: Dong
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Dong
authors.forename: Zongzhen
authors.initials: Z
authors.lastname: Xu
authors.forename: Huaqiang
authors.initials: H
authors.lastname: Zhu
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wei
authors.forename: Bo
authors.initials: B
authors.lastname: Zhai
authors.forename: Jagat R
authors.initials: JR
authors.lastname: Kanwar
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Xueying
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D051152:Clusterin / Q000378:metabolism* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D051152:Clusterin; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D051057:Proto-Oncogene Proteins c-akt