The extracellular matrix protein TGFBI induces microtubule stabilization and sensitizes ovarian cancers to paclitaxel

被引：196

作者：

Ahmed, Ahmed Ashour ^{[1
,3
,5
]}

Mills, Anthony D. ^{[4
]}

Ibrahim, Ashraf E. K. ^{[1
]}

Temple, Jillian ^{[1
,3
]}

Blenkiron, Cherie ^{[3
]}

Vias, Maria ^{[3
]}

Massie, Charlie E. ^{[3
]}

Iyer, N. Gopalakrishna ^{[3
]}

McGeoch, Adam ^{[4
]}

Crawford, Robin ^{[5
]}

Nicke, Barbara ^{[6
]}

Downward, Julian ^{[6
]}

Swanton, Charles ^{[6
]}

Bell, Stephen D. ^{[4
]}

Earl, Helena M. ^{[3
]}

Laskey, Ronald A. ^{[4
]}

Caldas, Carlos ^{[2
,3
]}

Brenton, James D. ^{[1
,3
]}

机构：

[1] Li Ka Shing Ctr, Canc Res UK Cambridge Res Inst, Funct Genom Drug Resistance Lab, Cambridge CB2 0RE, England

[2] Li Ka Shing Ctr, Canc Res UK Cambridge Res Inst, Breast Canc Funct Genom Lab, Cambridge CB2 0RE, England

[3] Hutchison MRC Res Ctr, Dept Oncol, Cambridge CB2 0XZ, England

[4] Hutchison MRC Res Ctr, MRC Canc Cell Unit, Cambridge CB2 0XZ, England

[5] Cambridge Univ Hosp, NHS Fdn Trust, Addenbrookes Hosp, Gynaecol Oncol Reg Ctr, Cambridge CB2 0QQ, England

[6] Canc Res UK London Res Inst, Signal Transduct Lab, London WC2A 3PX, England

来源：

CANCER CELL | 2007年 / 12卷 / 06期

基金：

英国医学研究理事会;

关键词：

D O I：

10.1016/j.ccr.2007.11.014

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The extracellular matrix (ECM) can induce chemotherapy resistance via AKT-mediated inhibition of apoptosis. Here, we show that loss of the ECM protein TGFBI (transforming growth factor beta induced) is sufficient to induce specific resistance to paclitaxel and mitotic spindle abnormalities in ovarian cancer cells. Paclitaxel-resistant cells treated with recombinant TGFBI protein show integrin-dependent restoration of paclitaxel sensitivity via FAK- and Rho-dependent stabilization of microtubules. Immunohistochemical staining for TGFBI in paclitaxel-treated ovarian cancers from a prospective clinical trial showed that morphological changes of paclitaxel-induced cytotoxicity were restricted to areas of strong expression of TGFBI. These data show that ECM can mediate taxane sensitivity by modulating microtubule stability.

引用

页码：514 / 527

页数：14

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