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

Zhi-Qiang Yao,Xi-Feng Li,Bo Yang,Xian-Zhi Liu,Yongqi Zhen,Feng Gao,Xu-Ying He,Leilei Fu,Xin Zhang,Shuangmei Zhao,Chuan-Zhi Duan,Fu-You Guo

doi:10.1038/s41419-018-0799-z

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.

Highlights

Sirtuin-1 (SIRT1), a NAD+-dependent protein deacetylase, catalyzes the removal of acetyl groups from lysine residues in substrate proteins
Macroautophagy is the major regulated catabolic mechanism that involves the delivery of cytoplasmic cargo, which sequestered inside doublemembrane vesicles to the lysosome, highly regulated by a few autophagy-related signaling pathways, such as AMPK-mTOR-ULK1
To further demonstrate that SIRT1 is downregulated in brain cancer, we applied three tissue microarray (TMA) containing 70 samples of glioblastoma and 35 samples of normal brain tissues to evaluate the expression of SIRT1

Summary

Introduction

Sirtuin-1 (SIRT1), a NAD+-dependent protein deacetylase, catalyzes the removal of acetyl groups from lysine residues in substrate proteins. Yao et al Cell Death and Disease (2018)9:767 exacerbations, and the overexpression of SIRT1 was neuroprotective[6]. As autophagy is often regard as a survival mechanism, cancer cells could exploit it to survive nutrient limitation and hypoxia that often occur in solid tumors[9]. Several studies have demonstrated that autophagy-dependent cell death occurs under certain experimental conditions such as excessive cellular stress or treatment with chemotherapeutic agents or other toxic compounds[11,12]. Targeting autophagy is a significant therapeutic avenue in cancer treatment

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Results

Conclusion