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

Background: We have reported that polydatin (PD) alleviates mitochondrial dysfunction in rat models of sepsisinduced acute kidney injury (SI-AKI), but the mechanism is not well understood. Here, we investigated the role of Parkin-mediated mitophagy in the protective effects of PD in SI-AKI in mice. Methods: Sepsis was induced in the mice by caecal ligation and puncture. Mitophagy was determined by mitochondrial mass. NLRP3 inflammasome activation was determined by NLRP3, ASC and caspase-1. Mitophagy was blocked by treatment with mitochondrial division inhibitor-1 and Parkin knockout. Key results: PD treatment increased the sepsis-induced loss of mitochondrial mass, indicating the upregulation of mitophagy. Furthermore, PD treatment mediated Parkin translocation from the cytoplasm to the mitochondria. This suggests that Parkin-mediated mitophagy is an underlying mechanism. This was confirmed by the suppression of PD-induced mitophagy in Parkin−/− mice and in mice that were treated with a mitophagy inhibitor. PD-induced Parkin translocation and mitophagy were blocked by inhibiting SIRT1; thus, activation of SIRT1 might be an important molecular mechanism that is triggered by PD. Additionally, PD treatment protected against sepsis-induced kidney injury. These effects were blocked by inhibition of Parkin-dependent mitophagy. Furthermore, PD also protected against mitochondrial dysfunction and mitochondria-dependent apoptosis, and the effect was blocked when Parkindependent mitophagy was inhibited. Finally, PD suppressed NLRP3 inflammasome activation that was also dependent on Parkin-mediated mitophagy. Conclusions: These findings indicate that Parkin-mediated mitophagy is important for the protective effect of PD in SI-AKI, and the underlying mechanisms include the inhibition of mitochondrial dysfunction and NLRP3 inflammasome activation.

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“…The association between SIRT1 and mitophagy has been previously reported [21,24]. For example, SIRT1 Fig.…”

Section: Discussionsupporting

confidence: 66%

Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury

Gao

Dai

et al. 2020

J Transl Med

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“…Our previous studies demonstrated that SIRT1 has a protective role in IVDD 31,32 . Furthermore, several studies revealed that SIRT1 plays a key role in mitophagy and apoptosis in a variety of aging-related diseases via SIRT1-Parkin-Mitohphagy pathway [33][34][35][36][37] . In present study, we showed that circERCC2 regulated the expression of SIRT1 by sponging miR-182-5p.…”

Section: Discussionmentioning

confidence: 99%

CircERCC2 ameliorated intervertebral disc degeneration by regulating mitophagy and apoptosis through miR-182-5p/SIRT1 axis

et al. 2019

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The molecular mechanism of intervertebral disc degeneration (IVDD) remains unclear. This study aimed to investigate the role of circular RNAs (circRNAs) in the pathogenesis of IVDD. We sued nucleus pulposus (NP) tissues of patients, tert-butyl hydroperoxide (TBHP) stimulated NP cells (NPCs), and IVDD rat model to explore the interaction between circERCC2 and miR-182-5p/SIRT1 axis. The results showed that downregulation of circERCC2 increased the level of miR-182-5p and decreased the level of SIRT1 in degenerative NP tissues in vivo as well as in TBHP-stimulated NPCs in vitro. Treatment of SIRT1-si activated apoptosis and inhibited mitophagy. Moreover, miR-182-5p-si could regulate the mitophagy and the apoptosis of NPCs by targeting SIRT1. The effects of circERCC2 on NPCs and IVDD rat model were mediated by miR-182-5p/SIRT1 axis. In conclusion, this study provides the first evidence that circERCC2 could ameliorate IVDD through miR-182-5p/SIRT1 axis by activating mitophagy and inhibiting apoptosis, and suggests that circERCC2 is a potentially effective therapeutic target for IVDD.

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“…Changes in SIRT1 expression levels are frequent molecular events in human cancers 11,[19][20][21] . Recent data have shown low expression levels of SIRT1 in human colon cancer, lung cancer, and glioblastoma.…”

Section: Discussionmentioning

confidence: 99%

“…The consequent chemoresistance to the abovementioned treatment leads to unsatisfactory survival of GC patients. Activators of SIRT1 have been evaluated in preclinical studies and were shown to be a promising therapeutic strategy for glioblastoma and multiple myeloma 21,24 . Furthermore, in lung and pancreatic cancer, activation of SIRT1 has been shown to enhance cancer cell sensitivity to classic chemotherapy 25,26 .…”

Section: Discussionmentioning

confidence: 99%

“…As metabolic sensors, SIRT1/AMPK signaling was shown to play important role in metabolism 33 . Recently, AMPK activated by SIRT1 is proven to act as a tumor suppressor in multiple solid tumors by inducing cell death, inhibiting cell migration, and attenuating hypoxia-induced chemoresistance 21,25,[34][35][36] . Our data demonstrated that silencing AMPKα partially reverses inhibitory role of SIRT1 in GC cells.…”

Section: Discussionmentioning

confidence: 99%

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SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop

Wang

et al. 2020

Cell Death Dis

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Chemotherapy is the standard care for patients with gastric cancer (GC); however, resistance to existing drugs has limited its success. The persistence of cancer stem cells (CSCs) is considered to be responsible for treatment failure. In this study, we demonstrated that SIRT1 expression was significantly downregulated in GC tissues, and that a low SIRT1 expression level indicated a poor prognosis in GC patients. We observed a suppressive role of SIRT1 in chemoresistance of GC both in vitro and in vivo. In addition, we found that SIRT1 eliminated CSC properties of GC cells. Mechanistically, SIRT1 exerted inhibitory activities on chemoresistance and CSC properties through FOXO3 and AMPK. Furthermore, a synergistic effect was revealed between FOXO3 and AMPK. AMPK promoted nuclear translocation of FOXO3 and enhanced its transcriptional activities. In addition, FOXO3 increased the expression level and activation of AMPKα by directly binding to its promoter and activating the transcription of AMPKα. Similar to SIRT1, low expression levels of p-AMPKα and FOXO3a are also related to the poor prognosis of GC patients. Moreover, we revealed a correlation between the expression levels of SIRT1, p-AMPKα, and FOXO3a. These findings indicated the importance of the SIRT1-AMPK/FOXO3 pathway in reversing chemoresistance and CSC properties of GC. Thus, exploring efficient strategies to activate the SIRT1-AMPK/FOXO3 pathway may lead to improving the survival of GC patients.

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

Cited by 90 publications

References 43 publications

Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury

Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury

CircERCC2 ameliorated intervertebral disc degeneration by regulating mitophagy and apoptosis through miR-182-5p/SIRT1 axis

SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop

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