Actin microfilament aggregation induced by withaferin A is mediated by annexin II

Abstract

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.

Withaferin A inhibits breast cancer invasion and metastasis at sub‐cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation

“…[29][30][31][32] WFA binds covalently to annexin II and stimulates its basal F-actin cross-linking activity 29 ; however, at the low nanomolar concentrations, we did not observe significant actin defects (Fig. 2a).…”

“…every other day 1 week after implantation of 4T1 cells. A dose range beginning with 0.1 mg/kg up to 4 mg/kg was selected based upon the PK analysis above and a previous report (29). The average body weight of control and WFA-treated mice did not differ significantly throughout the study (data not shown).…”

“…25 Moreover, WFA has proapoptotic and anti-tumor activity in breast and prostate cancers. [26][27][28] There are several other documented targets of WFA including NF-Kb, BCL-2, FOXO3A, Hsp90, phosphorylated STAT3 and annexin II 27,[29][30][31][32][33] ; however, the mechanisms by which this leads to anti-tumor activity are not fully understood.…”

Characterisation and protein expression profiling of annexins in colorectal cancer

“…Furthermore, while there has been a range of studies of individual annexin expression in specific types of primary tumours, there have been no significant previous studies of annexin expression in metastasis. In addition, more recently individual annexins have been proposed as putative tumour biomarkers and potential therapeutic targets in cancer (Oh et al, 2004;Falsey et al, 2006;Wozny et al, 2007). The expression and cellular localisation of annexins have received very little previous study in colorectal cancer, with only annexin A2 having been investigated (Emoto et al, 2001).…”

Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I–DNA complex

“…18,19 Withaferin A can alter cytoskeletal architecture by covalently binding annexin II and stimulating its basal F-actin crosslinking activity. 20 Leishmania, a unicellular kinetoplastid protozoan parasite, is the causative agent of leishmaniasis. With the spread of human immunodeficiency virus (HIV), the parasites pose a much greater threat than before.…”