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Blacksburg, VA, United States

Ketene A.N.,00 Randolph Hall | Roberts P.C.,Corporate Research Center Building | Shea A.A.,Corporate Research Center Building 23 | Schmelz E.M.,Corporate Research Center Building 23 | Agah M.,VT MEMS Laboratory
Integrative Biology | Year: 2012

This atomic force microscopy (AFM) study is devoted to the analysis of the mouse ovarian cancer cell's cytoskeleton components and the impact of both actin and microtubulin filaments on a cell's deformation behavior. Early stage, non-tumorigenic cancer cells show abundant well-organized cytoskeletal structures consisting of both actin and microtubule filaments. In sharp contrast, cells representing late and more aggressive stages of cancer display highly disorganized actin and microtubule structures. With the use of actin microfilament targeting drugs, together with the suberoylanilide hydroxamic acid (SAHA) and tubastatin A anti-cancer drugs, we modified the cell architectural framework and performed nano-indentation tests to evaluate cell elasticity and viscosity as a function of each biopolymer's weighted presence. Results demonstrate that both mechanical properties are heavily influenced by the levels and organization state of actin microfilaments; decreasing the actin organization of cells results in 85% and 79% decrease in cell elasticity and viscosity, respectively. In contrast, microtubule organization was shown to exert only marginal effects on either property. Furthermore, the anti-cancer drug, SAHA, was shown to exert little impact on the viscoelastic response of cancer cells. Finally, we report for the first time that tubastatin A, a specific HDAC6 inhibitor, increased cell elasticity as revealed by AFM tests without exerting drastic changes to the actin microfilament or microtubule networks. Our findings raise interest in a potential HDAC6 target that affects cellular mechanics just as effectively as the conventionally known cytoskeleton components. © 2012 The Royal Society of Chemistry.

Babahosseini H.,00 Randolph Hall | Babahosseini H.,VT MEMS Laboratory | Roberts P.C.,Corporate Research Center Building | Schmelz E.M.,Kraft Foods Inc. | Agah M.,VT MEMS Laboratory
Integrative Biology (United Kingdom) | Year: 2013

Cancer progression is associated with an increased deformability of cancer cells and reduced resistance to mechanical forces, enabling motility and invasion. This is important for metastases survival and outgrowth and as such could be a target for chemopreventive strategies. In this study, we determined the differential effects of exogenous sphingolipid metabolites on the elastic modulus of mouse ovarian surface epithelial cells as they transition to cancer. Treatment with ceramide or sphingosine-1-phosphate in non-toxic concentrations decreased the average elastic modulus by 21% (p ≤ 0.001) in transitional and 15% (p ≤ 0.02) in aggressive stages while exerting no appreciable effect on non-malignant cells. In contrast, sphingosine treatment on average increased the elastic modulus by 33% (p ≤ 0.0002) in aggressive cells while not affecting precursor cells. These results indicate that tumor-supporting sphingolipid metabolites act by making cells softer, while the anti-cancer metabolite sphingosine partially reverses the decreased elasticity associated with cancer progression. Thus, sphingosine may be a valid alternative to conventional chemotherapeutics in ovarian cancer prevention or treatment. © 2013 The Royal Society of Chemistry.

Babahosseini H.,VT MEMS Laboratory | Carmichael B.,University of Alabama | Strobl J.S.,VT MEMS Laboratory | Mahmoodi S.N.,University of Alabama | Agah M.,VT MEMS Laboratory
Biochemical and Biophysical Research Communications | Year: 2015

This work investigates the biomechanical properties of sub-cellular structures of breast cells using atomic force microscopy (AFM). The cells are modeled as a triple-layered structure where the Generalized Maxwell model is applied to experimental data from AFM stress-relaxation tests to extract the elastic modulus, the apparent viscosity, and the relaxation time of sub-cellular structures. The triple-layered modeling results allow for determination and comparison of the biomechanical properties of the three major sub-cellular structures between normal and cancerous cells: the up plasma membrane/actin cortex, the mid cytoplasm/nucleus, and the low nuclear/integrin sub-domains. The results reveal that the sub-domains become stiffer and significantly more viscous with depth, regardless of cell type. In addition, there is a decreasing trend in the average elastic modulus and apparent viscosity of the all corresponding sub-cellular structures from normal to cancerous cells, which becomes most remarkable in the deeper sub-domain. The presented modeling in this work constitutes a unique AFM-based experimental framework to study the biomechanics of sub-cellular structures. © 2015 Elsevier Inc. All rights reserved.

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