Pharmacological Activation of Sirt1 Ameliorates Polyglutamine-Induced Toxicity through the Regulation of Autophagy

Abstract

Intracellular accumulation of polyglutamine (polyQ)-expanded Huntingtin (Htt) protein is a hallmark of Huntington’s disease (HD). This study evaluated whether activation of Sirt1 by the anti-cancer agent, β-lapachone (β-lap), induces autophagy in human neuroblastoma SH-SY5Y cells, thereby reducing intracellular levels of polyQ aggregates and their concomitant cytotoxicity. Treatment of cells with β-lap markedly diminished the cytotoxicity induced by forced expression of Htt exon 1 containing a pathogenic polyQ stretch fused to green fluorescent protein (HttEx1(97Q)-GFP). β-lap increased autophagy in SH-SY5Y cells, as evidenced by the increased formation of LC3-II and autolysosomes. Furthermore, β-lap reduced HttEx1(97Q)-GFP aggregation, which was significantly prevented by co-incubation with 3-methyladenine, an inhibitor of autophagy. β-lap increased Sirt1 activity, as shown by the increased deacetylation of the Sirt1 substrates, PARP-1 and Atg5, and the nuclear translocation of FOXO1. Both the induction of autophagy and attenuation of HttEx1(97Q)-GFP aggregation by β-lap were significantly prevented by co-incubation with sirtinol, a general sirtuin inhibitor or by co-transfection with shRNA against Sirt1. The pro-autophagic actions of β-lap were further investigated in a transgenic Caenorhabditis elegans (C. elegans) line that expressed Q67 fused to cyanine fluorescent protein (Q67). Notably, β-lap reduced the number of Q67 puncta and restored Q67-induced defects in motility, which were largely prevented by pre-treatment with RNAi against sir-2.1, the C. elegans orthologue of Sirt1. Collectively, these data suggest that β-lap induces autophagy through activation of Sirt1, which in turn leads to a reduction in polyQ aggregation and cellular toxicity. Thus, β-lap provides a novel therapeutic opportunity for the treatment of HD.

The Prognostic Role of SIRT1-Autophagy Axis in Gastric Cancer

“…Recently, Ramalinga et al (2015) [35] demonstrated that miR-212 inhibits autophagy by inhibiting SIRT1 expression in prostate cancer cells, while transfection of cells with SIRT1 induced autophagy. In addition, SIRT1 could reduce polyglutamine cellular toxicity by inducing autophagy in SH-SY5Y cells [36]. So far, there have been no studies examining the relationship between the SIRT1 and autophagy in GC.…”

Curcumin inhibits autophagy and apoptosis in hypoxia/reoxygenation-induced myocytes

“…Additionally, overexpression of BNIP3 promoted apoptotic cell death (47,48). SIRT1, a nicotinamide adenine dinucleotide-dependent deacetylase, regulates critical metabolic and physiological processes, including autophagy (37). SIRT1 induces autophagy by forming a molecular complex with several autophagy-associated genes and directly deacetylating these components (49).…”

“…These results indicated that curcumin promoted cell survival through inhibiting the excessive activation of autophagy by H/R. Several molecular mechanisms, including beclin-1, BN IP3 and SI RT1, respond to the regulation of autophagy (35)(36)(37). Therefore, the present study examined the changes in the levels of these autophagy-associated proteins in myocytes during H/R.…”

Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1

“…Sirt1 knockdown suppresses autophagy; conversely, agents which activate Sirt1 tend to activate autophagy [35,83,84]. Sirt1 interacts with and directly deacetylates a number of the ATG proteins required for autophagy, including ATG5, ATG7, and ATG8 [35].…”