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.
Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
Pei-Wen
PW
Wang
Mohammad R
MR
Abedini
Li-Xing
LX
Yang
Ann-Ann
AA
Ding
Daniel
D
Figeys
Jang-Yang
JY
Chang
Benjamin K
BK
Tsang
Dar-Bin
DB
Shieh
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D018260:Gelsolin / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; 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 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018260:Gelsolin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C505407:CASP3 protein, human; D053148:Caspase 3; D002945:Cisplatin
XIAP; chemoresistance; cisplatin; gelsolin; head-and-neck cancer