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    Biomechanics

    (E-162) Defining the role of NUDIX5 as a mechanical regulator in ovarian cancer cells

    Friday, October 13, 2023
    9:30 AM – 10:30 AM PDT
    Location: Exhibit Hall - Row E - Poster # 162
    Introduction: Cancer is a complex disease that involves significant changes in the genetic makeup, energy metabolism, and mechanical properties of cells to promote tumorigenesis. Cancer metastasis requires cells to deform and migrate through confined spaces. However, mechanical regulators of cancer cells—molecules that control cell deformability and migration—remains unknown. If we could map the mechanical regulators of cancer cells, this would enable us to define new and complementary treatment strategies for cancer.

    Materials and Methods:

    To address the need to identify new and effective treatments for ovarian cancer, we developed a high throughput deformability screen testing 1280 compounds (Library of Pharmacologically Active Compounds), which revealed compounds that reduce filtration of human ovarian cancer (OVCAR5) cells through 10 µm pores. A connectivity analysis across the top drug hits was performed, which revealed NUDIX5 as a predicted mechanical regulator. Thus, we analyzed the expression of NUDIX5 in publicly available patient datasets. To test the hypothesis that NUDIX5 is a mechanical regulator through its role in producing nuclear ATP, we manipulated levels of NUDIX5 in human ovarian cancer cell lines and blocked NUDIX5 activity by treating cells with the chemical inhibitor TH5427.

    Results, Conclusions, and Discussions:

    Our deformability screen revealed NUDIX5, a member of the Nudix (nucleoside diphosphate linked moiety X) hydrolase superfamily, as a predicted regulator of cellular mechanical behaviors. Analyses of publicly available patient datasets revealed NUDIX5 is highly expressed across cancer types compared to normal tissues. Interestingly, knockdown of NUDIX5 or blockade of NUDIX5 activity reduced whole-cell ATP levels and caused cells to be more deformable. We also found that NUDIX5 regulates cellular and nuclear shape, stiffness, as well as pore migration. Taken together, these findings identify NUDIX5 as a mechanical regulator with implications for ovarian cancer progression and treatment.