Coix Seed Oil Exerts an Anti–Triple-Negative Breast Cancer Effect by Disrupting miR-205/S1PR1 Axis

Ting Fang,Long Chen,Dale G Nagle,Dan-Dan Zhang,Yi-Xin Jiang,Yu-Dong Zhou,Ling Huang,Xin-Hui Tian

doi:10.3389/fphar.2020.529962

Abstract

Coix Seed Oil (CSO) possesses a wide range of pharmacological activities. Kanglaite Injection, a commercial product of CSO, has been used clinically as an anticancer drug in China for decades. However, its molecular mechanisms on triple-negative breast cancer (TNBC) remains to be elucidated. In this study, the effect of CSO was evaluated on murine TNBC 4T1 cells and the orthotopic tumor-bearing mouse model and underlying mechanisms were explored. CSO suppressed cell proliferation, colony formation in vitro, and tumor growth in vivo. miR-205-5p was substantially altered in CSO treated tumor tissues compared to the control group by miRNA-sequencing analysis. Sphingomyelin metabolism (SM) decreased in serum in model group compared to the control group, while it increased by CSO administration by lipid metabolomics analysis. The expression of sphingosine 1 phosphate receptor 1 (S1PR1), the critical effector of SM, was downregulated upon CSO treatment. Mechanically, miRNA-205 directly targeted S1PR1 to regulate SM and cell proliferation. CSO reduced the expression of S1PR1, cyclinD1, and phosphorylation levels of STAT3, MAPK, and AKT while upregulated p27. These results revealed that CSO exerted an anti-TNBC effect via the miR-205/S1PR1 axis to regulate sphingomyelin metabolism, and the downstream STAT3/MAPK/AKT signal pathways were partly involved.

Highlights

Breast cancer still incurs high morbidity and mortality globally and poses a severe health threat to women in recent years (Bray et al, 2018; Miller et al, 2019)
liquid-chromatography-mass spectrometry (LC-MS) was performed to determine the main ingredients in Coix Seed Oil (CSO)
The results showed six components including 1, 2Dilinoleoyl-3-palmitoyl-rac-glycerol, 1, 2- Dilinoleoyl-3-oleoylrac-glycerol, 1-palmitoyl-2-oleoyl-3-linoleoyl-rac-glycerol, 1, 2Dioleoyl-3-linoleoyl-rac-glycerol, 1, 2-Dioleoyl-3-palmitoyl-racglycerol and Glycerol trioleate existed in CSO

Summary

Introduction

Breast cancer still incurs high morbidity and mortality globally and poses a severe health threat to women in recent years (Bray et al, 2018; Miller et al, 2019). Cytotoxic chemotherapy plays an essential role in treating TNBC patients with severe side effects, drug resistance, and poor patient compliance. Traditional Chinese Medicine (TCM) presents advantages including reducing toxicity and side effects, increasing the sensitivity of drugs, and improving immune responses in numerous cancers treatments. Kanglaite Injection® (KLT) (Lu et al, 2008), a microemulsified injectable product derived from CSO, has been widely used to treat various tumors such as NSCLC (Duan, 2018; Wu et al, 2018), hepatocellular carcinoma (Yang et al, 2018), breast cancer (Guo et al, 2008), pancreatic (Liu et al, 2014; Schwartzberg et al, 2017) and gastric cancer (Zhang et al, 2017). KLT presented antineoplastic effect, reduced the side effects, and improved the quality of life such as cancer pain relief, cancer cachexia syndrome in patients (Liu et al, 2019; Zhang et al, 2019). Its exact antitumor mechanism, especially in TNBC, is still unclear

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Conclusion