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Hirudin inhibits glioma growth through mTOR-regulated autophagy |
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| Authors: | Ying Ma Senbin Wu Fanyi Zhao Huifeng Li Qiaohong Li Jingzhi Zhang Hua Li Zhongmin Yuan |
| Institution: | 1. Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou, China Contribution: Conceptualization (equal), Data curation (lead), Funding acquisition (equal), Methodology (lead), Software (lead), Validation (lead), Writing - original draft (lead);2. Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou, China Contribution: Methodology (equal), Software (equal), Validation (equal);3. Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou, China Contribution: Data curation (supporting);4. Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China Contribution: Supervision (supporting);5. Laboratory animal center, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China Contribution: Methodology (supporting);6. Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China |
| Abstract: | Glioma is the most common primary malignant brain tumour, and survival is poor. Hirudin has anticancer pharmacological effects through suppression of glioma cell progression, but the molecular target and mechanism are poorly understood. In this study, we observed that hirudin dose- and time-dependently inhibited glioma invasion, migration and proliferation. Mechanistically, hirudin activated LC3-II but not Caspase-3 to induce the autophagic death of glioma cells by decreasing the phosphorylation of mTOR and its downstream substrates ULK1, P70S6K and 4EBP1. Furthermore, hirudin inhibited glioma growth and induced changes in autophagy in cell-derived xenograft (CDX) nude mice, with a decrease in mTOR activity and activation of LC3-II. Collectively, our results highlight a new anticancer mechanism of hirudin in which hirudin-induced inhibition of glioma progression through autophagy activation is likely achieved by inhibition of the mTOR signalling pathway, thus providing a molecular basis for hirudin as a potential and effective clinical drug for glioma therapy. |
| Keywords: | apoptosis autophagy glioma Hirudin mTOR |