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5-Aza-2′-deoxycytidine increases hypoxia tolerance-dependent autophagy in mouse neuronal cells by initiating the TSC1/mTOR pathway

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机构： [a]Department of Neurobiology and Center of Stroke, Beijing Institute for Brain Disorders, School of Basic Medical Science, Capital Medical University, Beijing, China [b]Inner Mongolia Key laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, China [c]Beijing key laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China [d]Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, USA [e]Department of neurosurgery, the First Affiliated Hospital of Baotou Medical College, Inner Mongolia, China

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关键词： 5-Aza-2′-deoxycytidine Autophagy Hypoxia tolerance TSC1

摘要：

Background: Our previous study found that 5-Aza-2′-deoxycytidine (5-Aza-CdR) can repress the expression and activity of protein serine/threonine phosphatase-1γ (PP1γ) in mouse hippocampus. It is well known that PP1γ regulates cell metabolism, which is related to hypoxia/ischaemia tolerance. It has been reported that it can also induce autophagy in cancer cells. Autophagy is important for maintaining cellular homeostasis associated with metabolism. In this study, we examined whether 5-Aza-CdR increases hypoxia tolerance-dependent autophagy by initiating the TSC1/mTOR/autophagy signalling pathway in neuronal cells. Methods: 5-Aza-CdR was either administered to mice via intracerebroventricular injection (i.c.v) or added to cultured hippocampal-derived neuronal cell line (HT22 cell) in the medium for cell culture. The hypoxia tolerance of mice was measured by hypoxia tolerance time and Perl's iron stain. The mRNA and protein expression levels of tuberous sclerosis complex 1 (TSC1), mammalian target of rapamycin (mTOR) and autophagy marker light chain 3 (LC3) were measured by real-time PCR and western blot. The p-mTOR and p-p70S6k proteins were used as markers for mTOR activity. In addition, the role of autophagy was determined by correlating its intensity with hypoxia tolerance in a time-dependent manner. At the same time, the involvement of the TSC1/mTOR pathway in autophagy was also examined through transfection with TSC1 (hamartin) plasmid. Results: 5-Aza-CdR was revealed to increase hypoxia tolerance and induce autophagy, accompanied by an increase in mRNA and protein expression levels of TSC1, reduction in p-mTOR (Ser2448) and p-p70S6k (Thr389) protein levels, and an increase in the ratio of LC3-II/LC3-I in both mouse hippocampus and hippocampal-derived neuronal cell line (HT22). The fluorescence intensity of hamartin was enhanced in the hippocampus of mice exposed to 5-Aza-CdR. Moreover, HT22 cells that over-expressed TSC1 showed more autophagy. Conclusions: 5-Aza-CdR can increase hypoxia tolerance by inducing autophagy by initiating the TSC1/mTOR pathway. © 2019 The Authors

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出版当年[2018]版：

大类 | 3 区医学

小类 | 3 区医学：研究与实验 3 区药学

最新[2023]版：

大类 | 2 区

医学

小类 | 1 区药学 2 区医学：研究与实验

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出版当年[2017]版：

Q2 PHARMACOLOGY & PHARMACY Q2 MEDICINE, RESEARCH & EXPERIMENTAL

最新[2023]版：

Q1 MEDICINE, RESEARCH & EXPERIMENTAL Q1 PHARMACOLOGY & PHARMACY

影响因子： 6.9 最新[2023版] 6.8 最新五年平均 3.457 出版当年[2017版] 3.224 出版当年五年平均 2.759 出版前一年[2016版] 3.743 出版后一年[2018版]

第一作者：

第一作者机构： [a]Department of Neurobiology and Center of Stroke, Beijing Institute for Brain Disorders, School of Basic Medical Science, Capital Medical University, Beijing, China [b]Inner Mongolia Key laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, China [c]Beijing key laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China

通讯作者：

通讯机构： [a]Department of Neurobiology and Center of Stroke, Beijing Institute for Brain Disorders, School of Basic Medical Science, Capital Medical University, Beijing, China [b]Inner Mongolia Key laboratory of Hypoxic Translational Medicine, Baotou Medical College, Inner Mongolia, China [c]Beijing key laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China [*1]Department of Neurobiology and Center of Stroke, Beijing Institute for Brain Disorders, School of Basic Medical Science, Capital Medical University, Beijing, China

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5-Aza-2′-deoxycytidine increases hypoxia tolerance-dependent autophagy in mouse neuronal cells by initiating the TSC1/mTOR pathway

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