TPP-related mitochondrial targeting copper (II) complex induces p53-dependent apoptosis in hepatoma cells through ROS-mediated activation of Drp1

Abstract

BackgroundIn recent years, copper complexes have gradually become the focus of potential anticancer drugs due to their available redox properties and low toxicity. In this study, a novel mitochondrion-targeting copper (II) complex, [Cu (ttpy-tpp)Br2] Br (simplified as CTB), is first synthesized by our group. CTB with tri-phenyl-phosphine (TPP), a targeting and lipophilic group, can cross the cytoplasmic and mitochondrial membranes of tumor cells. The present study aims to investigate how CTB affects mitochondrial functions and exerts its anti-tumor activity in hepatoma cells.MethodsMultiple molecular experiments including Flow cytometry, Western blot, Immunofluorescence, Tracker staining, Transmission Electron Microscopy and Molecular docking simulation were used to elucidate the underlying mechanisms. Human hepatoma cells were subcutaneously injected into right armpit of male nude mice for evaluating the effects of CTB in vivo.ResultsCTB induced apoptosis via collapse of mitochondrial membrane potential (MMP), ROS production, Bax mitochondrial aggregation as well as cytochrome c release, indicating that CTB-induced apoptosis was associated with mitochondrial pathway in human hepatoma cells. Mechanistic study revealed that ROS-related mitochondrial translocation of p53 was involved in CTB-mediated apoptosis. Simultaneously, elevated mitochondrial Drp1 levels were also observed, and interruption of Drp1 activation played critical role in p53-dependent apoptosis. CTB also strongly suppressed the growth of liver cancer xenografts in vivo.ConclusionIn human hepatoma cells, CTB primarily induces mitochondrial dysfunction and promotes accumulation of ROS, leading to activation of Drp1. These stimulation signals accelerate mitochondrial accumulation of p53 and lead to the eventual apoptosis. Our research shows that CTB merits further evaluation as a chemotherapeutic agent for the treatment of Hepatocellular carcinoma (HCC).

Suppressing DRP1-mediated mitochondrial fission and mitophagy increases mitochondrial apoptosis of hepatocellular carcinoma cells in the setting of hypoxia

“…Besides inhibiting DRP1 phosphorylation, Mdivi-1 down-regulated DRP1 expression in this study. As reported by other authors 32,38 , inhibition of DRP1 by Mdivi-1 decreased the DRP1 expression in their experiments. Mdivi-1 is reported to have additional targets, which may be responsible for DRP1 down-regulation.…”

Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy

“…R-goniothalamin-induced abundant ROS reactivate the R175H mutant P53 protein in human breast cancer cells, and then P53 promotes the expression of pro-apoptotic proteins: p21cip1, BAX, and p53 upregulated modulator of apoptosis, causing tumor cell apoptosis 96 . ROS not only enhance the transcription effect of P53 but also translocate P53 to mitochondria, contributing to BAX mitochondrial recruitment and mitochondrial Cyt c release, thus leading to cancer cell apoptosis 126 . In addition, the accumulation of ROS can trigger cancer cell DNA damage, and ROS-induced DNA damage causes the activation of DNA damage sensors and regulators such as ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR), thus activating P53 and subsequently leading to cancer cell apoptosis 127 , 128 .…”

Novel copper complex CTB regulates methionine cycle induced TERT hypomethylation to promote HCC cells senescence via mitochondrial SLC25A26

“…We used the human hepatoma cell line Huh-7 to establish a subcutaneous xenograft model to verify the correlation in vivo. Because our recent research clearly shows that CTB has a powerful anti-hepatocellular carcinoma effect in vivo 27,36 . We focus on proving whether the role of CTB depends on regulating SLC25A26 in this section.…”