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Cell Death Dis. 2018 Jul 10;9(7):767. doi: 10.1038/s41419-018-0799-z.

A novel small-molecule activator of Sirtuin-1 induces autophagic cell death/mitophagy as a potential therapeutic strategy in glioblastoma.

Author information

1
The National Key Clinical Specialty, The Engineering Technology Research Center of Education of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
2
Department of Interventional Neuroradiology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou, 450052, China.
3
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.
4
Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou, 450052, China.
5
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China. leilei_fu@163.com.
6
Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou, 450052, China. liuxianzhi2@sina.com.
7
The National Key Clinical Specialty, The Engineering Technology Research Center of Education of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China. Doctor_duanzj@163.com.

Abstract

Sirtuin-1 (SIRT1), the mammalian ortholog of yeast Sir2p, is well known to be a highly conserved NAD+-dependent protein deacetylase that has been emerging as a key cancer target. Autophagy, an evolutionarily conserved, multi-step lysosomal degradation process, has been implicated in cancer. Accumulating evidence has recently revealed that SIRT1 may act as a tumor suppressor in several types of cancer, and thus activating SIRT1 would represent a possible therapeutic strategy. Thus, in our study, we identified that SIRT1 was a key prognostic factor in brain cancer based upon The Cancer Genome Atlas and tissue microarray analyses. Subsequently, we screened a series of potential small-molecule activators of SIRT1 from Drugbank, and found the best candidate compound F0911-7667 (hereafter, named Comp 5), which showed a good deacetylase activity for SIRT1 rather than other Sirtuins. In addition, we demonstrated that Comp 5-induced autophagic cell death via the AMPK-mTOR-ULK complex in U87MG and T98G cells. Interestingly, Comp 5-induced mitophagy by the SIRT1-PINK1-Parkin pathway. Further iTRAQ-based proteomics analyses revealed that Comp 5 could induce autophagy/mitophagy by downregulating 14-3-3γ, catalase, profilin-1, and HSP90α. Moreover, we showed that Comp 5 had a therapeutic potential on glioblastoma (GBM) and induced autophagy/mitophagy by activating SIRT1 in vivo. Together, these results demonstrate a novel small-molecule activator of SIRT1 that induces autophagic cell death/mitophagy in GBM cells, which would be utilized to exploit this compound as a leading drug for future cancer therapy.

PMID:
29991742
PMCID:
PMC6039470
DOI:
10.1038/s41419-018-0799-z
[Indexed for MEDLINE]
Free PMC Article

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