2.50
Hdl Handle:
http://hdl.handle.net/10033/332603
Title:
Targeting the actin cytoskeleton: selective antitumor action via trapping PKCɛ.
Authors:
Foerster, F; Braig, S; Moser, C; Kubisch, R; Busse, J; Wagner, E; Schmoeckel, E; Mayr, D; Schmitt, S; Huettel, S; Zischka, H; Mueller, R; Vollmar, A M
Abstract:
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 quite elusive. We used the myxobacterial compound Chondramide as a tool to first elucidate the mechanisms 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-ɛ (PKCɛ), 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. PKCɛ, 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 PKCɛ, we suggest that trapping PKCɛ via Chondramide-induced actin hyperpolymerization displays tumor cell specificity. Our work provides a link between targeting the ubiquitously occurring actin CSK and selective inhibition of pro-tumorigenic PKCɛ, thus setting the stage for actin-stabilizing agents as innovative cancer drugs. This is moreover supported by the in vivo efficacy of Chondramide triggered by abrogation of PKCɛ signaling shown in a xenograft breast cancer model.
Citation:
Targeting the actin cytoskeleton: selective antitumor action via trapping PKCɛ. 2014, 5:e1398 Cell Death Dis
Journal:
Cell death & disease
Issue Date:
2014
URI:
http://hdl.handle.net/10033/332603
DOI:
10.1038/cddis.2014.363
PubMed ID:
25165884
Type:
Article
Language:
en
ISSN:
2041-4889
Appears in Collections:
publications of the department of microbial natural substances ([HIPS]MINS)

Full metadata record

DC FieldValue Language
dc.contributor.authorFoerster, Fen
dc.contributor.authorBraig, Sen
dc.contributor.authorMoser, Cen
dc.contributor.authorKubisch, Ren
dc.contributor.authorBusse, Jen
dc.contributor.authorWagner, Een
dc.contributor.authorSchmoeckel, Een
dc.contributor.authorMayr, Den
dc.contributor.authorSchmitt, Sen
dc.contributor.authorHuettel, Sen
dc.contributor.authorZischka, Hen
dc.contributor.authorMueller, Ren
dc.contributor.authorVollmar, A Men
dc.date.accessioned2014-10-09T14:01:36Z-
dc.date.available2014-10-09T14:01:36Z-
dc.date.issued2014-
dc.identifier.citationTargeting the actin cytoskeleton: selective antitumor action via trapping PKCɛ. 2014, 5:e1398 Cell Death Disen
dc.identifier.issn2041-4889-
dc.identifier.pmid25165884-
dc.identifier.doi10.1038/cddis.2014.363-
dc.identifier.urihttp://hdl.handle.net/10033/332603-
dc.description.abstractTargeting 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 quite elusive. We used the myxobacterial compound Chondramide as a tool to first elucidate the mechanisms 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-ɛ (PKCɛ), 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. PKCɛ, 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 PKCɛ, we suggest that trapping PKCɛ via Chondramide-induced actin hyperpolymerization displays tumor cell specificity. Our work provides a link between targeting the ubiquitously occurring actin CSK and selective inhibition of pro-tumorigenic PKCɛ, thus setting the stage for actin-stabilizing agents as innovative cancer drugs. This is moreover supported by the in vivo efficacy of Chondramide triggered by abrogation of PKCɛ signaling shown in a xenograft breast cancer model.en
dc.language.isoenen
dc.rightsArchived with thanks to Cell death & diseaseen
dc.titleTargeting the actin cytoskeleton: selective antitumor action via trapping PKCɛ.en
dc.typeArticleen
dc.identifier.journalCell death & diseaseen

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