The actin targeting compound Chondramide inhibits breast cancer metastasis via reduction of cellular contractility.
BACKGROUND
A major player in the process of metastasis is the actin cytoskeleton as it forms key structures in both invasion mechanisms, mesenchymal and amoeboid migration. We tested the actin binding compound Chondramide as potential anti-metastatic agent.


METHODS
In vivo, the effect of Chondramide on metastasis was tested employing a 4T1-Luc BALB/c mouse model. In vitro, Chondramide was tested using the highly invasive cancer cell line MDA-MB-231 in Boyden-chamber assays, fluorescent stainings, Western blot and Pull down assays. Finally, the contractility of MDA-MB-231 cells was monitored in 3D environment and analyzed via PIV analysis.


RESULTS
In vivo, Chondramide treatment inhibits metastasis to the lung and the migration and invasion of MDA-MB-231 cells is reduced by Chondramide in vitro. On the signaling level, RhoA activity is decreased by Chondramide accompanied by reduced MLC-2 and the stretch induced guanine nucleotide exchange factor Vav2 activation. At same conditions, EGF-receptor autophosphorylation, Akt and Erk as well as Rac1 are not affected. Finally, Chondramide treatment disrupted the actin cytoskeleton and decreased the ability of cells for contraction.


CONCLUSIONS
Chondramide inhibits cellular contractility and thus represents a potential inhibitor of tumor cell invasion.
Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany.
Magdalena H
MH
Menhofer
Department of Pharmacy, Pharmaceutical Biotechnology, University of Munich, Munich, Germany.
Rebekka
R
Kubisch
Department of Pharmacy, Pharmaceutical Biotechnology, University of Munich, Munich, Germany.
Laura
L
Schreiner
Department of Physics, Soft Matter Physics and Biophysics, University of Munich, Munich, Germany.
Matthias
M
Zorn
Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany.
Florian
F
Foerster
Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany.
Rolf
R
Mueller
Department of Physics, Soft Matter Physics and Biophysics, University of Munich, Munich, Germany.
Joachim O
JO
Raedler
Department of Pharmacy, Pharmaceutical Biotechnology, University of Munich, Munich, Germany.
Ernst
E
Wagner
Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany.
Angelika M
AM
Vollmar
Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany.
Stefan
S
Zahler
D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D024722:Cardiac Myosins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D003285:Contractile Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007275:Injections, Intravenous; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D003285:Contractile Proteins; D047630:Depsipeptides; D018994:Myosin Light Chains; D010456:Peptides, Cyclic; D051567:Proto-Oncogene Proteins c-vav; C490565:Vav2 protein, mouse; C097819:chondramide A; C107184:myosin light chain 2; D024722:Cardiac Myosins; D020742:rhoA GTP-Binding Protein