CoQ0-induced mitochondrial PTP opening triggers apoptosis via ROS?mediated VDAC1 upregulation in HL-60 leukemia cells and suppresses tumor growth in athymic nude mice/xenografted nude mice

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Title:	CoQ0-induced mitochondrial PTP opening triggers apoptosis via ROS?mediated VDAC1 upregulation in HL-60 leukemia cells and suppresses tumor growth in athymic nude mice/xenografted nude mice
Authors:	許游章;Hseu, You-Cheng;Varadharajan;Thiyagarajan, Varadharajan;Ou, Ting Tsz;Ou, Ting Tsz;;Ya, Hsin Ling;Yang, Hsin Ling;
Contributors:	食品營養與保健生技學系
Date:	2018-01
Issue Date:	2018-08-20 01:47:31 (UTC+0)
Abstract:	Coenzyme Q (CoQ) analogs with variable numbers of isoprenoid units have been demonstrated as anticancer and antioxidant/pro-oxidant molecules. This study examined the in vitro and in vivo antitumor and apoptosis activities of CoQ0 (2,3-dimethoxy-5-methyl-1,4-benzoquinone, zero isoprenoid side-chains) through upregulation of the Voltage-dependent anion channel 1 (VDAC1) signaling pathway on human promyelocytic leukemia. CoQ0 (0-40 μg/mL) treatment significantly reduced HL-60 cell viability, and up-regulated mitochondrial VDAC1 expression. CoQ0 treatment triggers intracellular ROS generation, calcium release, ΔΨm collapse and PTP opening in HL-60 cells. CoQ0 treatment induced apoptosis, which was associated with DNA fragmentation, cytochrome c release, caspase-3 and PARP activation, and Bax/Bcl-2 dysregulation. Annexin V-PI staining indicated that CoQ0 promotes late apoptosis. Furthermore, the blockade of CoQ0-induced ROS production by antioxidant NAC pretreatment substantially attenuated CoQ0-induced apoptosis. The activation of p-GSK3β expression, cyclophilin D inhibition, and p53 activation through ROS are involved in CoQ0-induced HL-60 apoptotic cell death. Notably, ROS-independent p38 activation is involved in CoQ0-mediated apoptosis in HL-60 cells. In addition, the silencing of VDAC1 also prevented CoQ0-induced mitochondrial translocation of Bax, activation of caspase-3, and reduction in Bcl-2. Intriguingly, VDAC1 silencing did not prevent ROS production induced by CoQ0, which in turn indicates that CoQ0 induced ROS-mediated VDAC1 and then mitochondrial apoptosis in HL-60 cells. In vivo results revealed that CoQ0 is effective in delaying tumor incidence and reducing the tumor burden in HL-60-xenografted nude mice. Taken together, CoQ0 could be a promising anticancer agent for the treatment of human promyelocytic leukemia through upregulation of VDAC1 signaling pathways. KEYWORDS: Apoptosis; CoQ0; PTP opening; ROS; VDAC1
Relation:	ARCHIVES OF TOXICOLOGY
Appears in Collections:	[Department of Food Nutrition and Healthy Biotechnology] Journal Article

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