The Herbal Formula JI017 Induces ER Stress via Nox4 in Breast Cancer Cells.

Tae Woo Kim,Seong-Gyu Ko

doi:10.3390/antiox10121881

Abstract

Chemotherapy is a powerful anti-tumor therapeutic strategy; however, resistance to treatment remains a serious concern. To overcome chemoresistance, combination therapy with anticancer drugs is a potential strategy. We developed a novel herbal extract, JI017, with lower toxicity and lesser side effects. JI017 induced programmed cell death and excessive unfolded protein response through the release of intracellular reactive oxygen species (ROS) and calcium in breast cancer cells. JI017 treatment increased the expression of endoplasmic reticulum (ER) stress markers, including p-PERK, p-eIF2α, ATF4, and CHOP, via the activation of both exosomal GRP78 and cell lysate GRP78. The ROS inhibitors diphenyleneiodonium and N-acetyl cysteine suppressed apoptosis and excessive ER stress by inhibiting Nox4 in JI017-treated breast cancer cells. Furthermore, in paclitaxel-resistant breast cancer cell lines, MCF-7R and MDA-MB-231R, a combination of JI017 and paclitaxel overcame paclitaxel resistance by blocking epithelial-mesenchymal transition (EMT) processes, such as the downregulation of E-cadherin expression and the upregulation of HIF-1α, vimentin, Snail, and Slug expression. These findings suggested that JI017 exerts a powerful anti-cancer effect in breast cancer and a combination therapy of JI017 and paclitaxel may be a potential cancer therapy for paclitaxel resistant breast cancer.

Highlights

Our findings suggest that Nox4 is involved in endoplasmic reticulum (ER) stress and apoptotic cell death by reactive oxygen species (ROS) production in
We showed that JI017 or paclitaxel with JI017 potently induces ER stress and apoptotic cell death in paclitaxel resistant breast cancer cells and breast cancer cells
We suggested evidence that sensitivity of paclitaxel resistant breast cancer cells to this combination treatment correlates with epithelial-mesenchymal transition (EMT) process by blocking HIF-1α, vimentin, Snali, and Slug and by activating E-cadherin in paclitaxel resistant breast cancer cells

Summary

Introduction

Breast cancer is a leading cause of cancer-related deaths in women worldwide [1]. Breast cancer is often divided in non-invasive and invasive breast cancer, and invasive breast cancer has several subtypes [2]. Non-invasive breast cancer (ductal carcinoma), a rare type of breast cancer, is found in the ducts of the breast and cannot spread outside the breast. Invasive breast cancer is the most common type and can spread outside the breast. Inflammatory breast cancer is a rare type of invasive breast cancer and makes the skin of the breast look red and feel warm [3]. Triple-negative breast cancer is a subtype of breast cancer that lacks estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2) and spread faster than the other types [4]. Chemo-resistance is a well-known phenomenon that arises due to many factors, such as epigenetic changes, genetic mutations, and molecular mechanisms [6]

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