Targeting the actin cytoskeleton: selective antitumor action via trapping PKCɛ.

Targeting the actin cytoskeleton (CSK) of cancer cells offers a valuable strategy in cancer therapy. There are a number of natural compounds that interfere with the actin CSK, but the mode of their cytotoxic action and, moreover, their tumor-specific mechanisms are quiteelusive.We usedthe myxobacterial compound Chondramide as atool tofirst elucidate themechanisms of cytotoxicity of actin targeting in breast cancer cells (MCF7, MDA-MB-231). Chondramide inhibits cellular actin filament dynamics shown by a fluorescence-based analysis (fluorescence recovery after photobleaching (FRAP)) and leads to apoptosis characterized by phosphatidylserine exposure, release of cytochrome C from mitochondria and finally activation of caspases. Chondramide enhances the occurrence of mitochondrial permeability transition (MPT) by affecting known MPT modulators: Hexokinase II bound to the voltage-dependent anion channel (VDAC) translocated from the outer mitochondrial membrane to the cytosol and the proapoptotic protein Bad were recruited to the mitochondria. Importantly, protein kinase C-e (PKCe), a prosurvival kinase possessing an actin-binding site and known to regulate the hexokinase/VDAC interaction as well as Bad phosphorylation was identified as the link between actin CSK and apoptosis induction. PKCe, which was found overexpressed in breast cancer cells, accumulated in actin bundles induced by Chondramide and lost its activity. Our second goal was to characterize the potential tumor-specific action of actin-binding agents. As the nontumor breast epithelial cell line MCF-10A in fact shows resistance to Chondramide-induced apoptosis and notably express low level of PKCe, we suggest that trapping PKCe via Chondramide-induced actin hyperpolymerization displays tumor cell specificity. Our work provides a link between targeting theubiquitously occurring actin CSK and selective inhibition of pro-tumorigenic PKCe, thussettingthe stage for actin-stabilizing agentsas innovativecancer drugs. This ismoreover supportedby theinvivoefficacyof Chondramide triggered by abrogation of PKCe signaling shown in a xenograft breast cancer model. Cell Death and Disease (2014) 5, e1398; doi:10.1038/cddis.2014.363; published online 28 August 2014