Nano-mechanical Reinforcement in Drug-Resistant Ovarian Cancer Cells

Abstract

The mechanical properties of cells are considered promising biomarkers for the early detection of cancer and the testing of drug efficacy against it. Nevertheless, generalized correlations between drug resistance and the nano-mechanical properties of cancer cells are yet to be defined due to the lack of necessary studies. In this study, we conducted atomic force microscopy (AFM)-based nano-mechanical measurements of cisplatinsensitive (A2780) and cisplatin-resistant (A2780cis) ovarian cancer cells. The difference in the efficacy of cisplatin between A2780 and A2780cis was confirmed in the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. We observed that the cisplatin-resistant ovarian cancer cells were more motile than cisplatin-sensitive cells based on the results of the wound closure experiment, and the AFM experiments showed that drug resistance induced nano-mechanical stiffening of the ovarian cancer cells. Increased mechanical stiffness caused by cisplatin resistance was consistent with the confocal microscopy images showing more distinct actin stress fibers in A2780cis than in A2780 cells. The down regulation of vinculin implicated the actin-driven elongation as a major motile mode for A2780cis cells. Our results consistently indicated that the acquisition of drug resistance in ovarian cancer cells induces an extensive reorganization of the actin cytoskeleton, which governs the cellular mechanical properties, motility, and possibly intracellular drug transportation.Key words atomic force microscopy (AFM); ovarian cancer; drug resistance; Young's modulus; nanomechanics Ovarian cancer is the leading cause of cancer-related mortality in gynecological malignancies. Little or no specific symptom at the early stage of ovarian cancer hinders the early diagnosis and contributes to the high mortality rate.1) The standard treatment of ovarian cancer is cytoreduction surgery, followed by platinum-based chemotherapy. However, most patients experience re-occurrence of cancer within 2 years of the initial treatment because of cancer cells' acquisition of resistance against platinum-based chemotherapy. A 5-year survival rate of the advanced ovarian cancer patients is reported to be only about 30%, 2) and the acquisition of cisplatin resistance is recognized as a major obstacle against the successful treatment of ovarian cancer. There are still many unresolved questions about how cancer cells become desensitized to chemotherapy.Recent advances in biomechanical studies suggest that the cellular mechanical compliance plays a crucial role in tumorigenesis and cancer progression. [3][4][5] In recent years, atomic force microscopy (AFM) is finding more attention in the field of biology and pharmaceutics.6-8) Especially, AFM-based nano-mechanics is recognized as a useful tool for detecting mechanical responses from local nanometer-sized domains of a cell.9-11) Changes in mechanical properties during pathological progressions have been investigated using AFM, 12,13) and abnorm...

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