Abstract
Dormant carcinoma cancer cells showing epithelial characteristics can be activated to dissipate into the surrounding tissue or organs through epithelial-mesenchymal transition (EMT). However, the molecular details underlying the activation of dormant cancer cells have been less explored. In this study, we examined the molecular pathway to activate dormant breast cancer cells. Rho-associated kinase (ROCK) inhibition disrupted cell junction, promoted cell proliferation and migration / invasion in both two-dimensional and three-dimensional substrates. The disintegration of cell junction upon ROCK inhibition, coupled with the loss of E-cadherin and b-catenin from the cell membrane, was associated with the activation of Rac1 upon ROCK inhibition. Migration / invasion also increased upon ROCK inhibition. However, the activation of MCF-7 cells upon ROCK inhibition was not associated with the up-regulation of typical EMT markers, such as snail and slug. Based on these results, we suggest the potential risk for dormant cancer cells to dissipate through non-typical EMT when ROCK activity is down-regulated.
Highlights
Dormant carcinoma cancer cells showing epithelial characteristics can be activated to dissipate into the surrounding tissue or organs through epithelial-mesenchymal transition (EMT)
In the assays of proliferation and migration, which are consistent with our conjecture that cellular responsiveness to Rho-associated kinase (ROCK) inhibition is dependent on cellular activity, the activating effect of ROCK inhibition was effective for the low active epithelial MCF-7 cells but not for the metastatic MDA-MB-231 cells [Fig 1]
This study demonstrates that ROCK inhibition induces MCF-7 dormant breast cancer cells to disseminate through the disintegration of cell junctions concomitant with increased cell proliferation, migration, and invasion when cultured on 2D or 3D substrates
Summary
Dormant carcinoma cancer cells showing epithelial characteristics can be activated to dissipate into the surrounding tissue or organs through epithelial-mesenchymal transition (EMT). The activation of MCF-7 cells upon ROCK inhibition was not associated with the up-regulation of typical EMT markers, such as snail and slug. Based on these results, we suggest the potential risk for dormant cancer cells to dissipate through non-typical EMT when ROCK activity is down-regulated. ROCK inhibition promotes cell proliferation through the down-regulation of phosphatase and tension homolog (PTEN) and the up-regulation of Akt phosphorylation [10,11] or accelerates cell migration through the activation of Rac1 [12]. We demonstrated that the inhibition of ROCK activates dormant MCF-7 breast cancer cells of which ROCK activity is dependent on the adhesion strength. The potential undesirable effect of ROCK inhibition on the activation of dormant cancer cells is of interest, as ROCK inhibition has recently been considered for the control of cardiovascular diseases ascribed for the prevention of contracting cells [14,15,16,17]
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