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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Antineoplastic Agents, Phytogenic / pharmacology
-
Cell Adhesion / drug effects
-
Cell Death / drug effects
-
Cell Line, Tumor
-
Centrosome / drug effects
-
Centrosome / metabolism
-
Drug Resistance, Neoplasm / drug effects
-
Extracellular Matrix Proteins / deficiency
-
Extracellular Matrix Proteins / metabolism*
-
Female
-
Fibronectins / metabolism
-
Gene Silencing / drug effects
-
Humans
-
Integrins / metabolism
-
Microtubules / drug effects*
-
Microtubules / metabolism*
-
Mitosis / drug effects
-
Models, Biological
-
Ovarian Neoplasms / metabolism*
-
Ovarian Neoplasms / pathology
-
Paclitaxel / pharmacology*
-
Protein Transport / drug effects
-
Recombinant Proteins / metabolism
-
Transforming Growth Factor beta / deficiency
-
Transforming Growth Factor beta / metabolism*
-
Tubulin / metabolism
Substances
-
Antineoplastic Agents, Phytogenic
-
Extracellular Matrix Proteins
-
Fibronectins
-
Integrins
-
Recombinant Proteins
-
Transforming Growth Factor beta
-
Tubulin
-
betaIG-H3 protein
-
Paclitaxel