Actin microfilament aggregation induced by withaferin A is mediated by annexin II.
The actin cytoskeleton supports diverse cellular processes such as endocytosis, oriented growth, adhesion and migration. The dynamic nature of the cytoskeleton, however, has made it difficult to define the roles of the many accessory molecules that modulate actin organization, especially the multifunctional adapter protein annexin II. We now report that the compound withaferin A (1) can alter cytoskeletal architecture in a previously unknown manner by covalently binding annexin II and stimulating its basal F-actin cross-linking activity. Drug-mediated disruption of F-actin organization is dependent on annexin II expression by cells and markedly limits their migratory and invasive capabilities at subcytotoxic concentrations. Given the extensive ethnobotanical history of withaferin-containing plant preparations in the treatment of cancer and inflammatory and neurological disorders, we suggest that annexin II represents a feasible, previously unexploited target for therapeutic intervention by small-molecule drugs.
Falsey
Ryan R
RR
Marron
Marilyn T
MT
Gunaherath
G M Kamal B
GM
Shirahatti
Nikhil
N
Mahadevan
Daruka
D
Gunatilaka
A A Leslie
AA
Whitesell
Luke
L
D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D000199:Actins / Q000378:metabolism; D000818:Animals; D017306:Annexin A2 / Q000378:metabolism*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001665:Binding Sites; D002417:Cattle; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004875:Ergosterol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008840:Microfilament Proteins / Q000378:metabolism*; D009422:Nervous System Diseases / Q000188:drug therapy; D013997:Time Factors; D054358:Withanolides
D000199:Actins; D017306:Annexin A2; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D008840:Microfilament Proteins; D054358:Withanolides; C009684:withaferin A; D004875:Ergosterol