Gelsolin regulates cisplatin sensitivity in human head-and-neck cancer.
Chemoresistance is a major challenge in cancer therapy. Cisplatin is commonly used for chemotherapy in patients with head-and-neck cancer (HNC), but it increases control of the disease by only 10-15%. Downregulation of proapoptotic pathways is a key determinant for chemoresistance in which gelsolin (GSN) is critically involved. We analyzed the association between GSN expression and cisplatin resistance in HNC cell lines, animals with HNC and cancer tissue samples from 58 cisplatin-treated patients with HNC. GSN expression levels were positively associated with chemoresistance in vitro and in vivo. Cisplatin-induced GSN downregulation was associated with the cleavage of GSN and the promotion of apoptosis. GSN silencing facilitated cisplatin-induced apoptosis in chemoresistant cells. In contrast, intact gelsolin was prosurvival in the presence of cisplatin by interacting with X-linked inhibitor of apoptosis protein (XIAP). In chemosensitive cells, cisplatin suppressed GSN-XIAP interaction, promoted translocation of XIAP from the perinuclear region to the nucleus and induced apoptosis. In chemoresistant cells, GSN was highly expressed, and cisplatin had no significant effect on GSN-XIAP interaction and apoptosis. We conclude that GSN is important for chemoresistance in HNC and may be an appropriate therapeutic target in chemoresistant cancers.
['Wang|Pei-Wen|PW|', 'Abedini|Mohammad R|MR|', 'Yang|Li-Xing|LX|', 'Ding|Ann-Ann|AA|', 'Figeys|Daniel|D|', 'Chang|Jang-Yang|JY|', 'Tsang|Benjamin K|BK|', 'Shieh|Dar-Bin|DB|']
D000818:Animals D000970:Antineoplastic Agents D017209:Apoptosis D053148:Caspase 3 D002945:Cisplatin D019008:Drug Resistance, Neoplasm D018260:Gelsolin D015972:Gene Expression Regulation, Neoplastic D020868:Gene Silencing D006258:Head and Neck Neoplasms D006801:Humans D008297:Male D053078:Membrane Potential, Mitochondrial D051379:Mice D016513:Mice, SCID D009364:Neoplasm Recurrence, Local D010641:Phenotype D020798:Two-Hybrid System Techniques D051636:X-Linked Inhibitor of Apoptosis Protein D023041:Xenograft Model Antitumor Assays
gelsolin cisplatin head-and-neck cancer chemoresistance XIAP