386613 Taxol Resistance Exacerbates Ovarian Cancer Progression By Altering Adhesion Kinetics and Strength

Wednesday, November 19, 2014
Galleria Exhibit Hall (Hilton Atlanta)
Daniel J. McGrail1, Niti Khambhati1, Krishan Patel2, Mark Qi2 and Michelle R. Dawson1, (1)Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, (2)Georgia Institute of Technology, Atlanta, GA

Ovarian cancer (OVCA) is the most lethal gynecological malignancy. Though the standard treatment protocol of tumor resection followed by chemotherapy has increased progression-free survival to nearly 18 months, once the cancer returns it is often no longer sensitive to these chemotherapeutic agents with survival rarely exceeding a year3. Of the two primary therapeutics used, one is microtubule-stabilizing Taxol. However, as a cytoskeletal filament, microtubules (MTs) also play a role in determining biomechanical properties of the cell. Since changes in ovarian cancer biomechanics have been shown to correlate with metastasis(1) responsible for 90% of deaths, we hypothesized that Taxol resistance may induce some of these changes ultimately exacerbating the disease’s malignancy. To investigate this, Taxol-resistant cell lines were isolated from parental ovarian cancer cell lines SKOV3 and OVCAR3 with a 10-fold increase in paclitaxel IC50. After isolating Taxol resistant cell lines, we initially quantified both their ability to efflux Rhodamine 123 as a model drug as well as if they gained any resistance to other chemotherapeutics and found negligible changes in both cases, suggesting there must be an alternative explanation to this resistance. Based on previous studies demonstrating increased MT dynamics (3) as well as the connection between MT dynamics (4) and adhesions, we hypothesized that the Taxol resistance may be gained partly by alteration in adhesive properties. We found that Taxol resistant cells adhered faster via higher integrin expression which may promote engraftment in secondary sites. Surprisingly, Taxol-resistant cells were less strongly adherent and displayed smaller focal adhesions possibly leading to increased shedding from the primary tumor. These larger and more stable mature focal adhesions may further slow focal adhesion turnover contributing to slower adhesion kinetics. Moreover, the faster adhesion speed coupled with decreased mature focal adhesions could increase focal adhesion turnover and expedite cell motility during metastasis. This work demonstrates that acquisition of Taxol resistance dramatically alters the adhesive ability of OVCA cells through differential expression both internal (paxillin) and external (integrin) adhesion proteins resulting in increased adhesion kinetics and decreased adhesion strength. Future work targeting these pathways may yield novel therapeutic targets that both slow metastatic cell engraftment and increase chemosensitivity.

 

References:
1. Swaminathan, V. Canc. Res. 2011. 71: 5075–80.
2. Reyes, CD. J. Biomed. Mater. Res. A. 2003. 67: 328–33
3. Gonçalves, D. Proc. Natl. Acad. Sci. U.S.A. 2001. 98: 11737–42.
4. Palazzo, AF. Science. 2004. 303: 836–9.


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