The role of gelsolin in head-and-neck cancer drug resistance and its molecular mechanisms
博士 === 國立成功大學 === 基礎醫學研究所 === 102 === Gelsolin (GSN) is a cytoskeleton-associated protein that regulates actin dynamic and is aberrantly regulated in many tumor types. GSN promotes or inhibits apoptosis in vitro, depending on the pathological conditions and cell types. Cisplatin is commonly used for...
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ndltd-TW-102NCKU53250272019-05-15T21:42:46Z http://ndltd.ncl.edu.tw/handle/z8wcct The role of gelsolin in head-and-neck cancer drug resistance and its molecular mechanisms Gelsolin對頭頸癌化療抗藥性之影響及其分子機制之探討 Pei-WenWang 王佩文 博士 國立成功大學 基礎醫學研究所 102 Gelsolin (GSN) is a cytoskeleton-associated protein that regulates actin dynamic and is aberrantly regulated in many tumor types. GSN promotes or inhibits apoptosis in vitro, depending on the pathological conditions and cell types. 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%. Recent evidence indicates that down-regulation of the apoptotic pathways is a key determinants for cisplatin resistance. Dysregulation of pro-apoptotic [e.g. Fas, caspases and p53] and anti-apoptotic [e.g. Akt, X-linked inhibitor of apoptosis protein (XIAP), FLICE-like inhibitory protein (FLIP)] pathways have been found in chemoresistant cancer cells. Downregulation of pro-apoptotic pathways is a key determinant for chemoresistance in which GSN is critically involved. We hypothesized that gelsolin serve as a mobile docking protein interacts with intracellular intermediates and cross-talks with their signaling pathways to determine whether cells are sensitive or resistant to chemotherapy. In this study, high GSN expression in the 58 cisplatin-treated patients with HNC and 102 ovarian cancer (OVCA) patients were observed which were compared to their recurrence status after therapeutic with cisplatin. We analyzed the association between GSN expression and cisplatin resistance in HNC cell lines and animals 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 GSN (I-GSN) was pro-survival in the presence of cisplatin by interacting with 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. Dar-Bin Shieh 謝達斌 2014 學位論文 ; thesis 109 en_US |
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博士 === 國立成功大學 === 基礎醫學研究所 === 102 === Gelsolin (GSN) is a cytoskeleton-associated protein that regulates actin dynamic and is aberrantly regulated in many tumor types. GSN promotes or inhibits apoptosis in vitro, depending on the pathological conditions and cell types. 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%. Recent evidence indicates that down-regulation of the apoptotic pathways is a key determinants for cisplatin resistance. Dysregulation of pro-apoptotic [e.g. Fas, caspases and p53] and anti-apoptotic [e.g. Akt, X-linked inhibitor of apoptosis protein (XIAP), FLICE-like inhibitory protein (FLIP)] pathways have been found in chemoresistant cancer cells. Downregulation of pro-apoptotic pathways is a key determinant for chemoresistance in which GSN is critically involved. We hypothesized that gelsolin serve as a mobile docking protein interacts with intracellular intermediates and cross-talks with their signaling pathways to determine whether cells are sensitive or resistant to chemotherapy. In this study, high GSN expression in the 58 cisplatin-treated patients with HNC and 102 ovarian cancer (OVCA) patients were observed which were compared to their recurrence status after therapeutic with cisplatin. We analyzed the association between GSN expression and cisplatin resistance in HNC cell lines and animals 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 GSN (I-GSN) was pro-survival in the presence of cisplatin by interacting with 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.
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author2 |
Dar-Bin Shieh |
author_facet |
Dar-Bin Shieh Pei-WenWang 王佩文 |
author |
Pei-WenWang 王佩文 |
spellingShingle |
Pei-WenWang 王佩文 The role of gelsolin in head-and-neck cancer drug resistance and its molecular mechanisms |
author_sort |
Pei-WenWang |
title |
The role of gelsolin in head-and-neck cancer drug resistance and its molecular mechanisms |
title_short |
The role of gelsolin in head-and-neck cancer drug resistance and its molecular mechanisms |
title_full |
The role of gelsolin in head-and-neck cancer drug resistance and its molecular mechanisms |
title_fullStr |
The role of gelsolin in head-and-neck cancer drug resistance and its molecular mechanisms |
title_full_unstemmed |
The role of gelsolin in head-and-neck cancer drug resistance and its molecular mechanisms |
title_sort |
role of gelsolin in head-and-neck cancer drug resistance and its molecular mechanisms |
publishDate |
2014 |
url |
http://ndltd.ncl.edu.tw/handle/z8wcct |
work_keys_str_mv |
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