Alpha-mangostin induces endoplasmic reticulum stress and autophagy which count against fatty acid synthase inhibition mediated apoptosis in human breast cancer cells

Wenyuan Huang,Yan Liang,Xiaofeng Ma

doi:10.1186/s12935-019-0869-z

Abstract

Background/aimsOne of the most important metabolic hallmarks of breast cancer cells is enhanced lipogenesis. Increasing evidences suggest that fatty acid synthase (FAS) plays an important role in human breast cancer. Previously we discovered that alpha-mangostin showed apoptotic effect on human breast cancer cells via inhibiting FAS activity. The endoplasmic reticulum (ER) stress and autophagy are involved in cell apoptosis. However, the role of ER stress and autophagy in FAS inhibition induced apoptosis still remains unclear.MethodsWe evaluated the effects of alpha-mangostin on ER stress and autophagy in human breast cancer cells. Intracellular FAS activity was measured by a spectrophotometer at 340 nm of NADPH absorption. Cell Counting Kit assay was used to test the cell viability. Immunoblot analysis was performed to detect protein expression levels. Apoptotic effects were detected by flow cytometry.ResultsAlpha-mangostin induced endoplasmic reticulum stress and autophagy, both of which reduced the apoptotic effect of alpha-mangostin in MDA-MB-231 cells. Palmitic acid, the end product of FAS catalyzed reaction, rescued the ER stress and autophagy induced by alpha-mangostin. Cell apoptosis was markedly promoted by inhibiting ER stress and autophagy while treating cells with alpha-mangostin.ConclusionWe propose a hypothesis that a combination of FAS inhibition and ER stress and autophagy inhibition has an application potential in the chemoprevention and treatment of breast cancer.

Highlights

Breast cancer remains one of the most common human cancers and the second leading cause of cancer mortality in women worldwide [1]
Western blot results showed that after treating with α-mangostin, the ratio of LC3II/ LC3I was increased significantly, the expression level of P62 was significantly promoted in a dose-dependent manner, indicating that α-mangostin facilitated the autophagy level in MDA-MB-231 cells and MCF-7 cells, as is shown in Fig. 1b and Additional file 1: Figure S1
Cell viabilities were determined by the Cell Counting Kit (CCK-8) assay

Summary

Introduction

Breast cancer remains one of the most common human cancers and the second leading cause of cancer mortality in women worldwide [1]. Cancer cells acquire fatty acids mainly through de novo lipogenesis, in spite of sufficient dietary lipid supply, to support their growth and proliferation [3,4,5]. The endoplasmic reticulum (ER) is a place where proteins are modified in eukaryocyte cytoplasm and is the major site of lipid metabolism, as many enzymes. The unfold protein response (UPR) is a collection of signaling pathways that is activated to overcome the ER stress [11, 12]. Three ER transmembrane receptors, protein kinase R-like endoplasmic reticulum kinase (PERK), inositolrequiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6), initiate UPR through a signaling network [13]. Prolonged ER stress and activation of UPR pathways can lead to apoptosis and autophagy

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Conclusion