WITHDRAWN: Tannic acid, a secondary metabolite of higher plants, inhibits mammosphere formation of breast cancer cells via modulation of NF-κB pathway

Abstract

// Dal-Ah Kim 1, 2 , Hack Sun Choi 1, 2 , Eun-Sun Ryu 1, 2 , Jiyeon Ko 1, 2 , Heesung Chung 3 , Eun-Sung Jun 4 , Eok-Soo Oh 3 and Duk-Hee Kang 1, 2 1 The Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul 07985, Republic of Korea 2 Ewha Medical Research Center, Ewha Womans University School of Medicine, Seoul 07985, Republic of Korea 3 Department of Life Science, The Research Center Homeostasis, Ewha Womans University, Seoul 03760, Republic of Korea 4 Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, South Korea Correspondence to: Duk-Hee Kang, email: dhkang@ewha.ac.kr Keywords: cancer stem cells; tannic acid; mammosphere; NF-kB signaling; p65 Received: October 16, 2017      Accepted: January 03, 2018      Epub: January 02, 2018 ABSTRACT Cancer stem cells (CSCs) are known to mediate metastasis and recurrence, and are therefore a promising therapeutic target. Likewise, aberrant NF-κB signaling has been identified in many cancers, and shown to promote CSC formation via several mechanisms, including induction of epithelial-to-mesenchymal transition (EMT). Tannic acid (C76H52O46, TA) is reported to inhibit the proliferation of cancer cells, however there is no data regarding the effect of TA on CSCs. The present study investigated the effects of TA on CSC formation, NF-κB signaling, and EMT in breast cancer cells. TA inhibited the formation and growth of mammosphere in MCF7 cells expressed as a decrease in mammosphere formation efficiency (MFE) and ALDH1 activity. An activation of NF-κB pathway was observed in MCF7-derived mammosphere indicated by an up-regulation of p65, a degradation of IκBα and an increased IL-6. The inhibition of NF-κB pathway via gene silencing of p65 (sip65), NF-κB inhibitor (PDTC) and IKK inhibitor (Bay11-7082) alleviated MFE. Other markers of CSCs such as an increase in ALDH1 and the number of CD44 high /CD24 low cells were ameliorated by interfering p65. TA alleviated the markers of NF-κB activation in MCF7-derived mammosphere. TGFβ-induced EMT, increase in MFE and NF-κB activation was alleviated by TA. In in-vivo murine xenograft model, tumor volume was decreased by TA with a decrease in CD44 and IKK phosphorylation. Taken together, these results strongly suggest TA as a promising potential therapeutic agent capable of inhibiting NF-κB signaling in breast CSCs, and thereby preventing cancer cells from undergoing EMT and subsequent metastasis.