Regaining Taxol Sensitivity in Chemoresistant Ovarian Cancer Cells

Abstract

Ovarian cancer is a leading cause of death in women, and despite primary treatment, the majority of patients relapse. As the cancer becomes chemoresistant, prognosis dramatically worsens. Metastasis, or the spread of cancer, is the primary cause of death in more than 90% of ovarian cancers. Taxol, a frontline chemotherapeutic drug, works by stabilizing microtubules, cytoskeletal filaments required for cell division. While it is known that microtubules affect cell adhesion, it remains unclear if chemoresistance alters cell adhesion to the extracellular environment. We tested this by isolating Taxol-resistant cells, which displayed increased microtubule dynamics characterized by more rapid microtubule growth from fluorescently labeled EB3 microtubule protein. Additionally, they displayed faster adhesion rates and decreased adhesion strength, which could help overcome the rate-limiting step of metastasis. Adhesion strength was found to be independent of microtubule polymerization and dependent on up-regulated focal adhesion kinase (FAK) in the Taxol-resistant cells. Upon inhibition of FAK in these cells, microtubule dynamics decreased, signifying that adhesive signaling is up-stream of microtubule dynamics. Hence, by altering cell adhesion to the extracellular environment, Taxol-resistant cells show an increase in down-stream microtubule dynamics. This study consequently used FAK inhibition as a therapeutic target to improve prognosis by regaining drug sensitivity.