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Correlative nanomechanical profiling with super-resolution F-actin imaging reveals novel insights into mechanisms of cisplatin resistance in ovarian cancer cells

  • Shivani Sharma, PhD

      Affiliations

    • Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA
    • California NanoSystems Institute, University of California, Los Angeles, California, USA
    • Corresponding Author InformationCorresponding author: California Nanosystems Institute, 570 Westwood Plaza, University of California, Los Angeles, California 90095, USA.
    • ,
  • Chintda Santiskulvong, PhD

      Affiliations

    • Department of Obstetrics and Gynecology, University of California, Los Angeles, California, USA
    • ,
  • Laurent A. Bentolila, PhD

      Affiliations

    • Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA
    • California NanoSystems Institute, University of California, Los Angeles, California, USA
    • ,
  • JianYu Rao, MD

      Affiliations

    • Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California, USA
    • ,
  • Oliver Dorigo, MD, PhD

      Affiliations

    • Department of Obstetrics and Gynecology, University of California, Los Angeles, California, USA
    • ,
  • James K. Gimzewski, PhD

      Affiliations

    • Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA
    • California NanoSystems Institute, University of California, Los Angeles, California, USA
    • International Center for Materials Nanoarchitectonics Satellite (MANA), National Institute for Materials Science (NIMS), Tsukuba, Japan

Received 28 June 2011; accepted 24 September 2011. published online 24 October 2011.
Corrected Proof

Abstract 

The exact molecular mechanisms of ovarian cancer platinum resistance are not well understood, and biomarkers to reliably predict ovarian cancer resistance to platinum and other chemotherapeutic agents are lacking. Biomechanics of cisplatin-treated ovarian cancer cells were measured quantitatively at nanoscale level using atomic force microscopy. We demonstrate that cisplatin modulates the cellular nanomechanics of ovarian cancer cells; sensitive cells show dose-dependent increase in cell stiffness, which is effected by disrupting the F-actin polymerization. In contrast, resistant cells show no significant changes in cell stiffness upon cisplatin treatment. Further, stimulated emission depletion, an emerging super-resolution microscopy, shows that at the molecular level, F-actin is indeed remodeled considerably in cisplatin-sensitive and cisplatin-resistant cells. These findings reveal a direct role of the actin remodeling mechanism in cisplatin resistance of ovarian cancer cells, suggesting potential future applications of nanomechanical profiling as a marker for cancer drug sensitivity.

Graphical Abstract 

Organization of cellular F-actin cytoskeleton in cisplatin-resistant human ovarian cancer cell line OVCAR5-CisR revealed via STED microscopy, showing dense F-actin network with directionally oriented extensions through the cytoplasm up to the cell membrane.

Key words: Nanomechanics, Actin remodeling, Cisplatin resistance, Ovarian cancer, Stimulated emission depletion (STED)

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 This work was partially supported by funding from NIMS, Japan, and California Nanosystems Institute (CNSI) at UCLA. STED confocal laser scanning microscopy was performed on a Leica TCS SP5 STED confocal system at the CNSI Advanced Light Microscopy/Spectroscopy Laboratory at UCLA, supported with funding from NSF (MRI CHE-0722519).

PII: S1549-9634(11)00372-8

doi:10.1016/j.nano.2011.09.015

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