Quinocarmycin analog DX-52-1 inhibits cell migration and targets radixin, disrupting interactions of radixin with actin and CD44.
In the course of screening for new small-molecule modulators of cell motility, we discovered that quinocarmycin (also known as quinocarcin) analog DX-52-1 is an inhibitor of epithelial cell migration. While it has been assumed that the main target of DX-52-1 is DNA, we identified and confirmed radixin as the relevant molecular target of DX-52-1 in the cell. Radixin is a member of the ezrin/radixin/moesin family of membrane-actin cytoskeleton linker proteins that also participate in signal transduction pathways. DX-52-1 binds specifically and covalently to the C-terminal region of radixin, which contains the domain that interacts with actin filaments. Overexpression of radixin in cells abrogates their sensitivity to DX-52-1's antimigratory activity. Small interfering RNA-mediated silencing of radixin expression reduces the rate of cell migration. Finally, we found that DX-52-1 disrupts radixin's ability to interact with both actin and the cell adhesion molecule CD44.
Kahsai
Alem W
AW
Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269, USA.
Zhu
Shoutian
S
Wardrop
Duncan J
DJ
Lane
William S
WS
Fenteany
Gabriel
G
D000199:Actins / Q000378:metabolism*; D000818:Animals; D019921:Biotinylation; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D007313:Insecta; D007546:Isoquinolines / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D014162:Transfection
D000199:Actins; D003598:Cytoskeletal Proteins; D018960:Hyaluronan Receptors; D007546:Isoquinolines; D008565:Membrane Proteins; C071776:radixin; C091971:DX 52-1