title: Alterations in ovarian cancer cell adhesion drive taxol resistance by increasing microtubule dynamics in a FAK-dependent manner.
abstract: Chemorefractory ovarian cancer patients show extremely poor prognosis. Microtubule-stabilizing Taxol (paclitaxel) is a first-line treatment against ovarian cancer. Despite the close interplay between microtubules and cell adhesion, it remains unknown if chemoresistance alters the way cells adhere to their extracellular environment, a process critical for cancer metastasis. To investigate this, we isolated Taxol-resistant populations of OVCAR3 and SKOV3 ovarian cancer cell lines. Though Taxol-resistant cells neither effluxed more drug nor gained resistance to other chemotherapeutics, they did display increased microtubule dynamics. These changes in microtubule dynamics coincided with faster attachment rates and decreased adhesion strength, which correlated with increased surface β1-integrin expression and decreased focal adhesion formation, respectively. Adhesion strength correlated best with Taxol-sensitivity, and was found to be independent of microtubule polymerization but dependent on focal adhesion kinase (FAK), which was up-regulated in Taxol-resistant cells. FAK inhibition also decreased microtubule dynamics to equal levels in both populations, indicating alterations in adhesive signaling are up-stream of microtubule dynamics. Taken together, this work demonstrates that Taxol-resistance dramatically alters how ovarian cancer cells adhere to their extracellular environment causing down-stream increases in microtubule dynamics, providing a therapeutic target that may improve prognosis by not only recovering drug sensitivity, but also decreasing metastasis.
authors.affiliation: School of Chemical &Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: McGrail
authors.affiliation: School of Chemistry &Biochemistry, Georgia Institute of Technology, Atlanta, GA.
authors.forename: Niti N
authors.initials: NN
authors.lastname: Khambhati
authors.affiliation: School of Chemical &Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA.
authors.forename: Mark X
authors.initials: MX
authors.lastname: Qi
authors.affiliation: School of Chemical &Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA.
authors.forename: Krishan S
authors.initials: KS
authors.lastname: Patel
authors.affiliation: School of Chemical &Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA.
authors.forename: Nithin
authors.initials: N
authors.lastname: Ravikumar
authors.affiliation: School of Chemistry &Biochemistry, Georgia Institute of Technology, Atlanta, GA.
authors.forename: Chandler P
authors.initials: CP
authors.lastname: Brandenburg
authors.affiliation: 1] School of Chemical &Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA [2] The Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Dawson
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019012:Integrin beta1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D017239:Paclitaxel