The extracellular matrix protein TGFBI induces microtubule stabilization and sensitizes ovarian cancers to paclitaxel.
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.
Ahmed
Ahmed Ashour
AA
Functional Genomics of Drug Resistance Laboratory, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Mills
Anthony D
AD
Ibrahim
Ashraf E K
AE
Temple
Jillian
J
Blenkiron
Cherie
C
Vias
Maria
M
Massie
Charlie E
CE
Iyer
N Gopalakrishna
NG
McGeoch
Adam
A
Crawford
Robin
R
Nicke
Barbara
B
Downward
Julian
J
Swanton
Charles
C
Bell
Stephen D
SD
Earl
Helena M
HM
Laskey
Ronald A
RA
Caldas
Carlos
C
Brenton
James D
JD
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D011994:Recombinant Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism; D000099222:betaIG-H3 Protein
D000972:Antineoplastic Agents, Phytogenic; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D016023:Integrins; D017239:Paclitaxel; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014404:Tubulin; D000099222:betaIG-H3 Protein