Physalin A, 13,14-Seco-16, 24-Cyclo-Steroid, Inhibits Stemness of Breast Cancer Cells by Regulation of Hedgehog Signaling Pathway and Yes-Associated Protein 1 (YAP1).

Yu-Chan Ko,Dong-Sun Lee,Hack Sun Choi,Ren Liu

doi:10.3390/ijms22168718

Yu-Chan Ko, Dong-Sun Lee + Show 2 more

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https://doi.org/10.3390/ijms22168718

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Abstract

The Hedgehog (HH) signaling pathway plays an important role in embryonic development and adult organ homeostasis. Aberrant activity of the Hedgehog signaling pathway induces many developmental disorders and cancers. Recent studies have investigated the relationship of this pathway with various cancers. GPCR-like protein Smoothened (SMO) and the glioma-associated oncogene (GLI1) are the main effectors of Hedgehog signaling. Physalin A, a bioactive substance derived from Physalis alkekengi, inhibits proliferation and migration of breast cancer cells and mammospheres formation. Physalin A-induced apoptosis and growth inhibition of mammospheres, and reduced transcripts of cancer stem cell (CSC) marker genes. Physalin A reduced protein expressions of SMO and GLI1/2. Down-regulation of SMO and GLI1 using siRNA inhibited mammosphere formation. Physalin A reduced mammosphere formation by reducing GLI1 gene expression. Down-regulation of GLI1 reduced CSC marker genes. Physalin A reduced protein level of YAP1. Down-regulation of YAP1 using siRNA inhibited mammosphere formation. Physalin A reduced mammosphere formation through reduction of YAP1 gene expression. Down-regulation of YAP1 reduced CSC marker genes. We showed that treatment of MDA-MB-231 breast cancer cells with GLI1 siRNA induced inhibition of mammosphere formation and down-regulation of YAP1, a Hippo pathway effector. These results show that Hippo signaling is regulated by the Hedgehog signaling pathway. Physalin A also inhibits the canonical Hedgehog and Hippo signaling pathways, CSC-specific genes, and the formation of mammospheres. These findings suggest that physalin A is a potential therapeutic agent for targeting CSCs.

Highlights

IntroductionBreast cancer (BC) is invasive cancer and involves different areas of the breast (lobules, ducts, and connective tissue) and shows different clinical outcomes
Physalin A inhibited the formation of Breast cancer stem cells (BCSCs) through down-regulating canonical Hedgehog signaling effectors such as SMO and GLI1
yesassociated protein 1 (YAP1) protein was shown to be associated with outcomes in patients with luminal A breast cancer [56]. These findings indicate that a better understanding of the crosstalk between these pathways may be shown as potential therapeutic strategies against BCSCs

Summary

Introduction

Breast cancer (BC) is invasive cancer and involves different areas of the breast (lobules, ducts, and connective tissue) and shows different clinical outcomes. Based on the cancer response, BC can be divided into estrogen receptor(ER)-positive, progesterone receptor (PR)-positive, ER/PR-positive, human epidermal growth factor receptor-2 (HER2)-positive, and triple-negative breast cancer (TNBC) [1]. Breast cancer stem cells (BCSCs) are a small population of BC cells that play a critical role in the metastasis of BC to other organs and are a leading cause of tumor progression and resistance against conventional therapy. Targeting BCSCs may be a potential approach for the treatment of BC. Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors that exhibit

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