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: Peng Xiu, Xuesong Dong, Xiaofeng Dong, Zongzhen Xu, Huaqiang Zhu, Feng Liu, Zheng Wei, Bo Zhai, Jagat R Kanwar, Hongchi Jiang, Jie Li, Xueying Sun
• Journal: Cancer science (Cancer Sci) Vol. 104 Issue 3 Pg. 375-82 (Mar 2013) ISSN: 1349-7006 [Electronic] England
• PMID: 23279642 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 Japanese Cancer Association.

Chemical References

• Antineoplastic Agents
• Clusterin
• Organoplatinum Compounds
• Oxaliplatin
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Apoptosis
• Carcinoma, Hepatocellular (drug therapy, metabolism)
• Cell Line, Tumor
• Clusterin (metabolism, pharmacology)
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms (drug therapy, metabolism)
• Male
• Mice
• Organoplatinum Compounds (therapeutic use)
• Oxaliplatin
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction