Abstract
Opposed to tubulin-binding agents, actin-binding small molecules have not yet become part of clinical tumor treatment, most likely due to the fear of general cytotoxicity. Addressing this problem, we investigated the long-term efficacy of sub-toxic doses of miuraenamide, an actin filament stabilizing natural compound, on tumor cell (SKOV3) migration. No cytotoxic effects or persistent morphological changes occurred at a concentration of miuraenamide of 20 nM. After 72 h treatment with this concentration, nuclear stiffness was increased, causing reduced migration through pores in a Boyden chamber, while cell migration and chemotaxis per se were unaltered. A concomitant time-resolved proteomic approach showed down regulation of a protein cluster after 56 h treatment. This cluster correlated best with the Wnt signaling pathway. A further analysis of the actin associated MRTF/SRF signaling showed a surprising reduction of SRF-regulated proteins. In contrast to acute effects of actin-binding compounds on actin at high concentrations, long-term low-dose treatment elicits much more subtle but still functionally relevant changes beyond simple destruction of the cytoskeleton. These range from biophysical parameters to regulation of protein expression, and may help to better understand the complex biology of actin, as well as to initiate alternative regimes for the testing of actin-targeting drugs.
Highlights
Actin, the most abundant protein in eukaryotic cells, has been mostly associated with migration processes and cell division since its discovery in the 1940 ́s1
SKOV3 cells were treated with increasing concentrations of Miuraenamide A (Miu) in order to identify a subtoxic concentration
By using chondramide, we elicited very specific effects on the differentiation of macrophages[19] or kinase signaling[16] at concentrations were an obvious destruction of the actin cytoskeleton and acute cytotoxic effects were still absent
Summary
The most abundant protein in eukaryotic cells, has been mostly associated with migration processes and cell division since its discovery in the 1940 ́s1 This made actin a putative anti-cancer target, and with the advent of actin binding compounds (cytochalasin D 19712, phalloidin 19753, latrunculin 19834, jasplakinolide 19945) the hope for a therapeutic option increased. Since numerous in vitro studies have been conducted with different actin binding compounds, which have greatly improved our understanding of the biology of actin. To date, this has not led to a clinically used therapeutic[6]. In the present work we have used miuraenamide, an actin filament stabilizing natural compound[9,12,13] at sub-toxic concentrations and investigated its long-term effects on migration and protein expression patterns of SKOV3 cells
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