title: The extracellular matrix protein TGFBI induces microtubule stabilization and sensitizes ovarian cancers to paclitaxel.
abstract: 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.
authors: Functional Genomics of Drug Resistance Laboratory, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors: Ahmed Ashour
authors: AA
authors: Ahmed
authors: Anthony D
authors: AD
authors: Mills
authors: Ashraf E K
authors: AE
authors: Ibrahim
authors: Jillian
authors: J
authors: Temple
authors: Cherie
authors: C
authors: Blenkiron
authors: Maria
authors: M
authors: Vias
authors: Charlie E
authors: CE
authors: Massie
authors: N Gopalakrishna
authors: NG
authors: Iyer
authors: Adam
authors: A
authors: McGeoch
authors: Robin
authors: R
authors: Crawford
authors: Barbara
authors: B
authors: Nicke
authors: Julian
authors: J
authors: Downward
authors: Charles
authors: C
authors: Swanton
authors: Stephen D
authors: SD
authors: Bell
authors: Helena M
authors: HM
authors: Earl
authors: Ronald A
authors: RA
authors: Laskey
authors: Carlos
authors: C
authors: Caldas
authors: James D
authors: JD
authors: Brenton
mesh_terms: 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
chemical_list: 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