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

• Published in: Cell death & disease Vol. 9; no. 7; pp. 767 - 14
• Main Authors: Yao, Zhi-qiang, Zhang, Xin, Zhen, Yongqi, He, Xu-Ying, Zhao, Shuangmei, Li, Xi-Feng, Yang, Bo, Gao, Feng, Guo, Fu-You, Fu, Leilei, Liu, Xian-Zhi, Duan, Chuan-Zhi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.07.2018; Springer Nature B.V
• Subjects: 13/109; 13/89; 14/63; 64/60; 82/51; 96; Animals; Antibodies; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Autophagy; Autophagy - drug effects; Autophagy - genetics; Biochemistry; Biodegradation; Biomedical and Life Sciences; Brain cancer; Cancer; Catalase; Cell Biology; Cell Culture; Cell death; Cell Line, Tumor; Female; Genomes; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - metabolism; Humans; Immunology; Life Sciences; Lysosomes; Mice; Mice, Inbred BALB C; Mitophagy; NAD; Parkin protein; Phagocytosis; Profilin; Profilins - genetics; Profilins - metabolism; Protein Kinases - genetics; Protein Kinases - metabolism; Proteomics; PTEN-induced putative kinase; SIRT1 protein; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Sirtuins; TOR protein; Tumor suppressor genes; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-0799-z

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.