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Secretory clusterin contributes to oxaliplatin resistance by activating Akt pathway in hepatocellular carcinoma

Xiu, Peng, Dong, Xuesong, Dong, Xiaofeng, Xu, Zongzhen, Zhu, Huaqiang, Liu, Feng, Wei, Zheng, Zhai, Bo, Kanwar, Jagat R., Jiang, Hongchi, Li, Jie and Sun, Xueying 2013, Secretory clusterin contributes to oxaliplatin resistance by activating Akt pathway in hepatocellular carcinoma, Cancer science, vol. 104, no. 3, pp. 375-382, doi: 10.1111/cas.12088.

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Title Secretory clusterin contributes to oxaliplatin resistance by activating Akt pathway in hepatocellular carcinoma
Author(s) Xiu, Peng
Dong, Xuesong
Dong, Xiaofeng
Xu, Zongzhen
Zhu, Huaqiang
Liu, Feng
Wei, Zheng
Zhai, Bo
Kanwar, Jagat R.
Jiang, Hongchi
Li, Jie
Sun, Xueying
Journal name Cancer science
Volume number 104
Issue number 3
Start page 375
End page 382
Total pages 8
Publisher Wiley-Blackwell
Place of publication Chichester, Eng.
Publication date 2013-03
ISSN 1349-7006
Keyword(s) Animals
Antineoplastic Agents
Apoptosis
Carcinoma, Hepatocellular
Cell Line, Tumor
Clusterin
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Humans
Liver Neoplasms
Male
Mice
Organoplatinum Compounds
Proto-Oncogene Proteins c-akt
Signal Transduction
Summary 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.
Language eng
DOI 10.1111/cas.12088
Field of Research 111299 Oncology and Carcinogenesis not elsewhere classified
1112 Oncology And Carcinogenesis
Socio Economic Objective 920102 Cancer and Related Disorders
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2012, Japanese Cancer Association
Persistent URL http://hdl.handle.net/10536/DRO/DU:30075683

Document type: Journal Article
Collection: School of Medicine
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