<i>In vitro</i>and<i>in vivo</i>anti-tumor activity of CoQ0 against melanoma cells: inhibition of metastasis and induction of cell-cycle arrest and apoptosis through modulation of Wnt/β-catenin signaling pathways

Abstract

// You-Cheng Hseu 1, 2 , Varadharajan Thiyagarajan 1 , Hsiao-Tung Tsou 3 , Kai-Yuan Lin 4 , Hui-Jye Chen 5 , Chung-Ming Lin 6 , Jiuun-Wang Liao 7 , Hsin-Ling Yang 3 1 Department of Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 402, Taiwan 2 Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan 3 Institute of Nutrition, China Medical University, Taichung 402, Taiwan 4 Department of Medical Research, Chi-Mei Medical Center, Tainan 710, Taiwan 5 Department of Biotechnology, Ming Chuan University, Taoyuan 333, Taiwan 6 Graduate Institute of Basic Medical Science, China Medical University, Taichung 402, Taiwan 7 Graduate Institute of Veterinary Pathology, National Chung-Hsing University, Taichung 402, Taiwan Correspondence to: Hsin-Ling Yang, e-mail: hlyang@mail.cmu.edu.tw Keywords: CoQ 0 , melanoma, Wnt/&beta;-catenin, apoptosis, metastasis Received: October 23, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: February 23, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: March 8, 2016 ABSTRACT Coenzyme Q 0 (CoQ 0 , 2,3-dimethoxy-5-methyl-1,4-benzoquinone), a novel quinone derivative, has been shown to modulate cellular redox balance. However, effect of this compound on melanoma remains unclear. This study examined the in vitro or in vivo anti-tumor, apoptosis, and anti-metastasis activities of CoQ 0 (0-20 &mu;M) through inhibition of Wnt/&beta;-catenin signaling pathway. CoQ 0 exhibits a significant cytotoxic effect on melanoma cell lines (B16F10, B16F1, and A2058), while causing little toxicity toward normal (HaCaT) cells. The suppression of &beta;-catenin was seen with CoQ 0 administration accompanied by a decrease in the expression of Wnt/&beta;-catenin transcriptional target c-myc, cyclin D1, and survivin through GSK3&beta;-independent pathway. We found that CoQ 0 treatment caused G 1 cell-cycle arrest by reducing the levels of cyclin E and CDK4. Furthermore, CoQ 0 treatment induced apoptosis through caspase-9/-3 activation, PARP degradation, Bcl-2/Bax dysregulation, and p53 expression. Notably, non- or sub-cytotoxic concentrations of CoQ 0 markedly inhibited migration and invasion, accompanied by the down-regulation of MMP-2 and -9, and up-regulation of TIMP-1 and -2 expressions in highly metastatic B16F10 cells. Furthermore, the in vivo study results revealed that CoQ 0 treatment inhibited the tumor growth in B16F10 xenografted nude mice. Histological analysis and western blotting confirmed that CoQ 0 significantly decreased the xenografted tumor progression as demonstrated by induction of apoptosis, suppression of &beta;-catenin, and inhibition of cell cycle-, apoptotic-, and metastatic-regulatory proteins. The data suggest that CoQ 0 unveils a novel mechanism by down-regulating Wnt/&beta;-catenin pathways and could be used as a potential lead compound for melanoma chemotherapy.