Vimentin Is a Novel Anti-Cancer Therapeutic Target; Insights from In Vitro and In Vivo Mice Xenograft Studies

Abstract

BackgroundVimentin is a ubiquitous mesenchymal intermediate filament supporting mechano-structural integrity of quiescent cells while participating in adhesion, migration, survival, and cell signaling processes via dynamic assembly/disassembly in activated cells. Soft tissue sarcomas and some epithelial cancers exhibiting “epithelial to mesenchymal transition” phenotypes express vimentin. Withaferin-A, a naturally derived bioactive compound, may molecularly target vimentin, so we sought to evaluate its effects on tumor growth in vitro and in vivo thereby elucidating the role of vimentin in drug-induced responses.Methods and FindingsWithaferin-A elicited marked apoptosis and vimentin cleavage in vimentin-expressing tumor cells but significantly less in normal mesenchymal cells. This proapoptotic response was abrogated after vimentin knockdown or by blockade of caspase-induced vimentin degradation via caspase inhibitors or overexpression of mutated caspase-resistant vimentin. Pronounced anti-angiogenic effects of Withaferin-A were demonstrated, with only minimal effects seen in non-proliferating endothelial cells. Moreover, Withaferin-A significantly blocked soft tissue sarcoma growth, local recurrence, and metastasis in a panel of soft tissue sarcoma xenograft experiments. Apoptosis, decreased angiogenesis, and vimentin degradation were all seen in Withaferin-A treated specimens.ConclusionsIn light of these findings, evaluation of Withaferin-A, its analogs, or other anti-vimentin therapeutic approaches in soft tissue sarcoma and “epithelial to mesenchymal transition” clinical contexts is warranted.

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

“…Lastly, WFA has vimentin-dependent, anti-angiogenic activity at doses that are 500 fold lower than doses showing anti-tumor activity. 21,24,25 Therefore, it is possible that this anti-angiogenic activity is due to inhibition of vimentin during endothelial cell motility, 48,49 though in our in vivo model we did not observe reduced angiogenesis with this treatment schedule and dosing (data not shown).…”

“…21,24 WFA induces apoptosis in vimentin expressing tumor cells but less in mesenchymal cells, and inhibits soft tissue sarcoma growth and local recurrence in xenograft experiments. 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.…”

Telomerase Suppresses Formation of ALT-Associated Single-Stranded Telomeric C-Circles

“…The PLS cell line (17) was cultured in a 1:1 mixture of Dulbecco's modified Eagle's medium (DMEM; high glucose) and F12 (Gibco) supplemented with 10% FBS (Gibco), 2 mmol/L L-Glutamine (Gibco), 1Â antibiotic/ antimycotic (Gibco; 100 U/mL penicillin, 100 mg/mL streptomycin, 0.25 mg/mL amphotericin B), and 1Â nonessential amino acids (Lonza). The LS2 cell line (18) was cultured in RPMI-1640 (Gibco) with 20% FBS, 1Â minimum essential medium (MEM) vitamin mix (BioWhittaker), 1Â insulin/transferrin/ethanolamine/selenium (ITES) (BioWhittaker), 1Â penicillin (100 U/mL)/streptomycin (100 mg/mL)/L-glutamine (292 mg/mL; Invitrogen), 1 mmol/L sodium pyruvate, and 1Â nonessential amino acids (Lonza).…”

Metastatic breast cancer cells in the bone marrow microenvironment: novel insights into oncoprotection

“…Upon EMT, actin stress fibers become remodeled in a manner that facilitates cellular motility [15]. The gain of vimentin, an intermediate filament protein that strengthens cellular integrity and promotes cell survival and migration, may facilitate the EMT process [16]. Mesenchymal-like cells are thought to have properties that allow for separation from the underlying connective tissue, and weak intercellular contact by the mesenchymal-like tumor cells facilitates migrational events [12, 14].…”