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.
Highlights
Comprising more than 50 histological subtypes, soft tissue sarcoma (STS) can be classified into two major groups: those with specific genetic alterations and relatively simple karyotypes, and those with complex, unbalanced aneuploid karyotypes [1], [2], [3], [4], [5], [6]
The majority of STS belong to the second group harboring aneuploid karyotypes; this group mainly consists of malignant fibrous histiocytoma (MFH, termed unclassified pleomorphic sarcoma [UPS]), leiomyosarcomas, malignant peripheral nerve sheath tumors (MPNST), and dedifferentiated or pleomorphic liposarcomas
Sarcoma cells are highly sensitive to WFA To evaluate the effect of WFA on complex karyotype STS we selected a panel of human STS cell lines representing fibrosarcoma (HT1080), leiomyosarcoma (SKLMS1), MPNST (STS26T), and high grade pleomorphic sarcoma/liposarcoma (PLS-1)
Summary
Comprising more than 50 histological subtypes, soft tissue sarcoma (STS) can be classified into two major groups: those with specific genetic alterations (translocations or point mutations) and relatively simple karyotypes, and those with complex, unbalanced aneuploid karyotypes [1], [2], [3], [4], [5], [6]. Enhanced understanding of the molecular aberrations driving the inception and progression of several STS subtypes belonging to the first group (e.g., c-Kit mutations in gastrointestinal stromal tumors [GIST] or the 17;22 translocation leading to PDGF-B overexpression in dermatofibrosarcoma protuberans; [DFSP]), has resulted in clinical applications of effective targeted therapies (e.g. Imatinib mesylate) with significantly improved outcome [6]. Such therapeutic advancements are very encouraging and highlight the need to identify other novel molecular targets in additional STS subtypes. 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
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