Anti-EMT properties of CoQ0 attributed to PI3K/AKT/NFKB/MMP-9 signaling pathway through ROS-mediated apoptosis

• Main Authors: Hsin-Ling Yang, Varadharajan Thiyagarajan, Pei-Chun Shen, Dony Chacko Mathew, Kai-Yuan Lin, Jiunn-Wang Liao, You-Cheng Hseu
• Format: Article
• Language: English
• Published: BMC 2019-05-01
• Series: Journal of Experimental & Clinical Cancer Research
• Subjects: CoQ0; TNBC; EMT; Metastasis; Human epidermal growth factor receptor 2; TGF-β1
• Online Access: http://link.springer.com/article/10.1186/s13046-019-1196-x

Abstract Background Breast cancer is the most prevalent cancer among women. In triple-negative breast cancer (TNBC) cells, a novel quinone derivative, coenzyme Q0 (CoQ0), promotes apoptosis and cell-cycle arrest. This study explored the anti-epithelial–mesenchymal transition (EMT) and antimetastatic attributes of CoQ0 in TNBC (MDA-MB-231). Methods Invasion, as well as MTT assays were conducted. Lipofectamine RNAiMAX was used to transfect cells with β-catenin siRNA. Through Western blotting and RT-PCR, the major signaling pathways’ protein expressions were examined, and the biopsied tumor tissues underwent immunohistochemical and hematoxylin and eosin staining as well as Western blotting. Results CoQ0 (0.5–2 μM) hindered tumor migration, invasion, and progression. Additionally, it caused MMP-2/− 9, uPA, uPAR, and VEGF downregulation. Furthermore, in highly metastatic MDA-MB-231 cells, TIMP-1/2 expression was subsequently upregulated and MMP-9 expression was downregulated. In addition, CoQ0 inhibited metastasis and EMT in TGF-β/TNF-α-stimulated non-tumorigenic MCF-10A cells. Bioluminescence imaging of MDA-MB-231 luciferase–injected live mice demonstrated that CoQ0 significantly inhibited metastasis of the breast cancer to the lungs and inhibited the development of tumors in MDA-MB-231 xenografted nude mice. Silencing of β-catenin with siRNA stimulated CoQ0-inhibited EMT. Western blotting as well as histological analysis established that CoQ0 reduced xenografted tumor development because apoptosis induction, cell-cycle inhibition, E-cadherin upregulation, β-catenin downregulation, and metastasis and EMT regulatory protein modulation were observed. Conclusions CoQ0 inhibited the progression of metastasis as well as EMT (in vitro and in vivo). The described approach has potential in treating human breast cancer metastasis.