2, 3-Dihydro-3β-methoxy Withaferin-A Lacks Anti-Metastasis Potency: Bioinformatics and Experimental Evidences

• Published in: Scientific reports Vol. 9; no. 1; pp. 17344 - 11
• Main Authors: Chaudhary, Anupama, Kalra, Rajkumar S., Malik, Vidhi, Katiyar, Shashank P., Sundar, Durai, Kaul, Sunil C., Wadhwa, Renu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-11-2019; Nature Publishing Group
• Subjects: 13/1; 14/34; 14/63; 631/80/84/2336; 692/308/153; 82/29; 82/51; 96/98; Antitumor activity; Bioinformatics; Cadherins; Cancer; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Cell Proliferation - drug effects; Cell Survival - drug effects; Computational Biology; Cytoskeleton; Cytotoxicity; Epithelial-Mesenchymal Transition - drug effects; Heterogeneous-Nuclear Ribonucleoprotein K - chemistry; Heterogeneous-Nuclear Ribonucleoprotein K - metabolism; Humanities and Social Sciences; Humans; MCF-7 Cells; Metastases; Metastasis; Models, Molecular; Molecular Docking Simulation; multidisciplinary; N-Cadherin; Oxidative stress; p53 Protein; Ribonucleoprotein K; Science; Science (multidisciplinary); Tumor suppressor genes; Vascular endothelial growth factor; Vimentin; Withanolides - chemical synthesis; Withanolides - chemistry; Withanolides - pharmacology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-53568-6

Withaferin-A is a withanolide, predominantly present in Ashwagandha (
Withania somnifera
). It has been shown to possess anticancer activity in a variety of human cancer cells
in vitro
and
in vivo
. Molecular mechanism of such cytotoxicity has not yet been completely understood. Withaferin-A and Withanone were earlier shown to activate p53 tumor suppressor and oxidative stress pathways in cancer cells. 2,3-dihydro-3β-methoxy analogue of Withaferin-A (3βmWi-A) was shown to lack cytotoxicity and well tolerated at higher concentrations. It, on the other hand, protected normal cells against oxidative, chemical and UV stresses through induction of anti-stress and pro-survival signaling. We, in the present study, investigated the effect of Wi-A and 3βmWi-A on cell migration and metastasis signaling. Whereas Wi-A binds to vimentin and heterogeneous nuclear ribonucleoprotein K (hnRNP-K) with high efficacy and downregulates its effector proteins, MMPs and VEGF, involved in cancer cell metastasis, 3βmWi-A was ineffective. Consistently, Wi-A, and not 3βmWi-A, caused reduction in cytoskeleton proteins (Vimentin, N-Cadherin) and active protease (u-PA) that are essential for three key steps of cancer cell metastasis (EMT, increase in cell migration and invasion).