TY - JOUR
T1 - Inhibition of breast cancer stem-like cells by a triterpenoid, ursolic acid, via activation of Wnt antagonist, sFRP4 and suppression of miRNA-499a-5p
AU - Mandal, Saurabh
AU - Gamit, Naisarg
AU - Varier, Lavanya
AU - Dharmarajan, Arun
AU - Warrier, Sudha
N1 - Funding Information:
SM and NG are thankful for the support in the form of a scholarship from Manipal Academy of Higher Education, India. This work was supported partly by funding from the Department of Biotechnology , India (No. BT/PR9235/MED/31/258/2014 ) and Indian Council of Medical Research , India (No. 90/24/2012-BMS ). This paper is dedicated to a personal sage, in Science, in Life, and in the best of meticulous critique of our papers and ideas together. My dear friend and partner in DDC4, now known as sFRP4, Professor Robert Friis, University of Bern, Switzerland. A spiritual light to me in Science. I miss you. 26/07/2020 Rest in harmony.
Publisher Copyright:
© 2020 Elsevier Inc.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021/1/15
Y1 - 2021/1/15
N2 - Breast cancer, one of the leading causes of death in the world, has been largely considered to be drug resistant because of a small population of drug refractory cells, the cancer stem cells (CSCs). The CSCs are tightly regulated by self-renewal pathways such as the Wnt pathway, which is further regulated by a gamut of microRNAs. In this study, we investigated the effect of ursolic acid (UA), a natural triterpene, on breast CSCs enriched from breast cancer cell lines, MCF7, MDA-MB-231 and T47D and analysed the interplay of the Wnt inhibitor, sFRP4 and an miRNA, miR-499a-5p, in mediating the effect of UA. By using caspase 3/7, ROS, migration, TCF/LEF and CAM assays, overexpressing and inhibiting miR-499a-5p and NanoString PanCancer analysis, we observed that UA had significant anti-CSC ability. There was a link between UA and Wnt/β-catenin pathway wherein, Wnt was suppressed by upregulation of the antagonist, sFRP4. Furthermore, expression of the oncogenic miR-499a-5p was substantially diminished in CSCs after UA treatment. Notably, the axis by which miR-499a-5p acts is via the TCF/LEF machinery of the Wnt/β-catenin pathway. Our findings indicate for the first time that UA can target breast CSCs via Wnt by suppressing miR-499a-5p and upregulating the Wnt antagonist, sFRP4.
AB - Breast cancer, one of the leading causes of death in the world, has been largely considered to be drug resistant because of a small population of drug refractory cells, the cancer stem cells (CSCs). The CSCs are tightly regulated by self-renewal pathways such as the Wnt pathway, which is further regulated by a gamut of microRNAs. In this study, we investigated the effect of ursolic acid (UA), a natural triterpene, on breast CSCs enriched from breast cancer cell lines, MCF7, MDA-MB-231 and T47D and analysed the interplay of the Wnt inhibitor, sFRP4 and an miRNA, miR-499a-5p, in mediating the effect of UA. By using caspase 3/7, ROS, migration, TCF/LEF and CAM assays, overexpressing and inhibiting miR-499a-5p and NanoString PanCancer analysis, we observed that UA had significant anti-CSC ability. There was a link between UA and Wnt/β-catenin pathway wherein, Wnt was suppressed by upregulation of the antagonist, sFRP4. Furthermore, expression of the oncogenic miR-499a-5p was substantially diminished in CSCs after UA treatment. Notably, the axis by which miR-499a-5p acts is via the TCF/LEF machinery of the Wnt/β-catenin pathway. Our findings indicate for the first time that UA can target breast CSCs via Wnt by suppressing miR-499a-5p and upregulating the Wnt antagonist, sFRP4.
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U2 - 10.1016/j.lfs.2020.118854
DO - 10.1016/j.lfs.2020.118854
M3 - Article
C2 - 33278391
AN - SCOPUS:85097377261
SN - 0024-3205
VL - 265
JO - Life Sciences
JF - Life Sciences
M1 - 118854
ER -
