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

ABSTRACT: Related research has recognized the vital role of methionine cycle metabolism in cancers. However, the role and mechanism of methionine cycle metabolism in hepatocellular carcinoma are still unknown. In this study, we found that [Cu(ttpy-tpp)Br2]Br (Referred to as CTB) could induce hepatocellular carcinoma cells senescence, which is a new copper complex synthesized by our research group. Interestingly, CTB induces senescence by inhibiting the methionine cycle metabolism of HCC cells. Furthermore, the inhibitory effect of CTB on the methionine cycle depends on mitochondrial carrier protein SLC25A26, which was also required for CTB-induced HCC cells senescence. Importantly, we found that CTB-induced upregulation of SLC25A26 could cause abnormal methylation of TERT and inhibited TERT expression, which is considered to be an essential cause of cell senescence. The same results were also obtained in vivo, CTB inhibits the growth of subcutaneously implanted tumors in nude mice and promoted the expression of senescence markers in tumor tissues, and interference with SLC25A26 partially offset the antitumor effect of CTB.

SUBMITTER: Jin C

PROVIDER: S-EPMC7548283 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Jin Chun C Li Yujia Y Su Ying Y Guo Zijian Z Wang Xiaoyong X Wang Shijun S Zhang Feng F Zhang Zili Z Shao Jiangjuan J Zheng Shizhong S

Cell death & disease 20201011 10

Related research has recognized the vital role of methionine cycle metabolism in cancers. However, the role and mechanism of methionine cycle metabolism in hepatocellular carcinoma are still unknown. In this study, we found that [Cu(ttpy-tpp)Br<sub>2</sub>]Br (Referred to as CTB) could induce hepatocellular carcinoma cells senescence, which is a new copper complex synthesized by our research group. Interestingly, CTB induces senescence by inhibiting the methionine cycle metabolism of HCC cells. ...[more]

PMID: 33041323

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Project description:BackgroundOsteoarthritis (OA) is an age-related disease characterised by the accumulation of senescent chondrocytes, which drives its pathogenesis and progression. Senescent cells exhibit distinct features, including mitochondrial dysfunction and the excessive accumulation and release of reactive oxygen species (ROS), which are highly correlated and lead to a vicious cycle of increasing senescent cells. Stem cell therapy has proven effective in addressing cellular senescence, however, it still has issues such as immune rejection and ethical concerns. Microvesicles (MVs) constitute the primary mechanism through which stem cell therapy exerts its effects, offering a cell-free approach that circumvents these risks and has excellent anti-ageing potential. Nonetheless, MVs have a short in vivo half-life, and their secretion composition varies considerably under diverse conditions. This study aims to address these issues by constructing a ROS-responsive hydrogel loaded with pre-stimulant MVs. Through responding to ROS levels this hydrogel intelligently releases MVs, and enhancing mitochondrial function in chondrocytes to improving cellular senescence.ResultWe employed Interferon-gamma (IFN-γ) as a stem cell-specific stimulus to generate IFN-γ-microvesicles (iMVs) with enhanced anti-ageing effects. Simultaneously, we developed a ROS-responsive carrier utilising 3-aminophenylboronic acid (APBA)-modified silk fibroin (SF) and polyvinyl alcohol (PVA). This carrier served to protect MVs, prolong longevity, and facilitate intelligent release. In vitro experiments demonstrated that the Hydrogel@iMVs effectively mitigated cell senescence, improved mitochondrial function, and enhanced cellular antioxidant capacity. In vivo experiments further substantiated the anti-ageing capabilities of the Hydrogel@iMVs.ConclusionThe effect of MVs can be significantly enhanced by appropriate pre-stimulation and constructing a suitable carrier. Therefore, we have developed a ROS-responsive hydrogel containing IFN-γ pre-stimulated iMVs to target the characteristics of ageing chondrocytes in OA for therapeutic purposes. Overall, this novel approach effectively improving mitochondrial dysfunction by regulating the balance between mitochondrial fission and fusion, and the accumulation of reactive oxygen species was reduced, finally, alleviates cellular senescence, offering a promising therapeutic strategy for OA.

Dataset Information

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

Publications

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

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