Abstract
BackgroundDispersal of glioblastoma (GBM) cells leads to recurrence and poor prognosis. Accordingly, molecular pathways involved in dispersal are potential therapeutic targets. The mitogen activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) pathway is commonly dysregulated in GBM, and targeting this pathway with MEK inhibitors has proven effective in controlling tumor growth. Since this pathway also regulates ECM remodeling and actin organization − processes crucial to cell adhesion, substrate attachment, and cell motility – the aim of this study was to determine whether inhibiting this pathway could also impede dispersal.MethodsA variety of methods were used to quantify the effects of the MEK inhibitor, PD0325901, on potential regulators of dispersal. Cohesion, stiffness and viscosity were quantified using a method based on ellipsoid relaxation after removal of a deforming external force. Attachment strength, cell motility, spheroid dispersal velocity, and 3D growth rate were quantified using previously described methods.ResultsWe show that PD0325901 significantly increases aggregate cohesion, stiffness, and viscosity but only when tumor cells have access to high concentrations of fibronectin. Treatment also results in reorganization of actin from cortical into stress fibers, in both 2D and 3D culture. Moreover, drug treatment localized pFAK at sites of cell-substratum adhesion. Collectively, these changes resulted in increased strength of substrate attachment and decreased motility, a decrease in aggregate dispersal velocity, and in a marked decrease in growth rate of both 2D and 3D cultures.ConclusionsInhibition of the MAPK/ERK pathway by PD0325901 may be an effective therapy for reducing dispersal and growth of GBM cells.
Highlights
Dispersal of glioblastoma (GBM) cells leads to recurrence and poor prognosis
Effects of PD0325901 on fibronectin matrix assembly (FNMA), actin organization and pFAK localization in primary GBM cells Studies have previously demonstrated a growthinhibitory role for PD0325901 in GBM [20]
Treatment resulted in a remarkable change in cell shape, treated cells (Fig. 1e) becoming flatter and larger than those treated with dimethyl sulfoxide (DMSO) (Fig. 1d)
Summary
Dispersal of glioblastoma (GBM) cells leads to recurrence and poor prognosis. molecular pathways involved in dispersal are potential therapeutic targets. A novel o-naphtoquinone, has been shown to inhibit expression of N-cadherin and to block invasion of breast cancer cells [7] Such drugs could be of potential benefit for glioblastoma given the correlation between increased N-cadherin expression in high-grade gliomas and tissue invasion [8]. Given the complexity and heterogeneity of the ECM, and the likelihood that glioma cells tune their integrin receptor fingerprint to match the local ECM microenvironment, drugs that modulate the ECM may prove effective in reducing dispersal Many of these drugs, including various corticosteroids, target the ECM as a by-product of the drugs’ principal actions. Identification of other drugs that can have similar effects but target pathways involved in modulating integrins and the ECM could be of therapeutic value
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