The Polyphenolic Compound Curcumin Conjugation with an Alkyne Moiety in the Process of Autophagy

Abstract

Curcumin is a hydrophobic polyphenol derived from turmeric: the rhizome of the herb Curcumalonga. Autophagy is an evolutionarily conserved process, in which cellular proteins and organelles are engulfed in autophagosome and then fuses with lysosome for degradation. Our previous study showed that Curcumin activates lysosome and induce autophagy through inhibition of AKT (protein kinase K, PKB)-mammalian target of rapamycin (mTOR) pathway. But whether Curucmin affects the fusion of autophagosome-lysosome is still not clear. Here, we used Curcumin-probe conjugation with an alkyne moiety to label mouse embryonic fibroblasts (MEFs) and found that Curcumin targets autophagy-related proteins, enhances autophagic flux and activates lysosome in cells. Moreover, Curcumin treatment promotes the fusion of autophasosome-lysosome in MEFs. Second, the enhanced fusion of autophagosome-lysosome is attributed to mTOR suppression. Third, blockage of the autophagosome-lysosome fusion leads to cell growth inhibition by Curcumin. Taken together, data from our study indicates the importance of the fusion of autophagosome-lysosome in Curcumin-induced autophagy, which may facilitate the development of Curcumin as a potential therapeutic agent for oxidative stress-related diseases.

Transcriptome profiling analysis reveals that ATP6V0E2 is involved in the lysosomal activation by anlotinib

“…5) and the post-translational regulation of TFEB became the most important mechanism regulating lysosomal function in anlotinib-treated cells. On the one hand, the lower phosphorylation levels of TFEB enhanced the transcriptional activity of TFEB 16,44 ; on the other hand, the inhibition of the TFEB phosphorylation decreased its degradation and thus increased its expression levels (Fig. 5a) 45 .…”

Role of Autophagy on Heavy Metal-Induced Renal Damage and the Protective Effects of Curcumin in Autophagy and Kidney Preservation

“…In addition, studies have proposed that curcumin acts in different ways depending on its concentration: At low concentrations it functions as an antioxidant, at medium concentrations it also acts as an autophagy inductor, however it has been reported in an in vitro experiment in cancer cell that curcumin at high concentrations leads to cell death [1,4,59,60]. Although the mechanisms by which curcumin induces autophagy were initially described in cancer cells [61], they also occur in normal cells [25]. Nevertheless, their effect differ between both cell types: In normal cells, curcumin mainly induces autophagy [62] in different ways to promote cell survival (see detail in Table 2).…”

“…In addition, curcumin not only participates in the early stage of autophagy, but also in the latter stage, such as in the fusion of autophagosomes and lysosomes, as well as in the degradation of autolysosomes [25,71]. Yan et al (2018) found in mouse embryonic fibroblasts (MEF) cells exposed to curcumin, enhanced autophagic flux and lysosomal function (lysosomal acidification and cathepsin B activity) and an increased autophagosome-lysosome fusion.…”

“…Yan et al (2018) found in mouse embryonic fibroblasts (MEF) cells exposed to curcumin, enhanced autophagic flux and lysosomal function (lysosomal acidification and cathepsin B activity) and an increased autophagosome-lysosome fusion. Lysosomal acidification by curcumin was achieved by upregulation of vacuolar V-ATPase gene expression [25]. Curcumin-induced autophagy activation was mediated by suppression of the AKT/mTOR pathway, although until now it is still under debate if the lysosomal function in autophagy depends on mTOR [25].…”

“…Adverse effects of heavy metals have been usually associated with oxidative stress, which involves an overproduction of reactive oxygen species (ROS) and the loss of the endogenous antioxidant defense, as well as with mitochondrial dysfunction [18,21]. However, it was recently found that heavy metals can also impair autophagy flux [22,23,24], an evolutionarily-conserved self-digestive process, which is generally considered to be a cell survival mechanism [25]. In vitro and in vivo studies related to the participation of autophagy in kidney damage have described that autophagy helps to remove damaged mitochondria, avoiding ROS overproduction and cellular damage [26,27].…”