Anti-MTOR monoclonal antibody, clone 64F22

In the last few decades, studies on autophagy regulation and its potential role in cancer therapeutics have expanded to include detailed mechanisms. Since apoptosis exhibits drug resistance in some cancers, efforts have focused on searching for compounds with autophagy modulating properties. Numerous natural compounds have been used in cancer treatment and are considered a significant research area due to their remarkable anti-cancer properties. Celastrol, a quinone methide triterpene, derived from Tripterygium wilfordii, has recently drawn much attention because of its anticancer potential. It enhances tumor suppression and induces autophagy in cancer cells by regulating signaling pathways such as Beclin-1, Akt/mTOR, ROS, NF-kappa B, MAPK, HSP90, and the proteasome. In the current study, we address the anticancer potential of celastrol, its effect on various cellular pathways, and describe how it functions as an autophagy modulator in cancer therapeutics and helps diminish multidrug resistance in cancer cells.

Perfluorooctane sulfonate (PFOS), a classic environmental pollutant, is reported to cause cardiotoxicity in animals and humans. It has been demonstrated that PFOS exposure down-regulates expression of cardiac-development related genes and proteins. However, the related mechanism of PFOS has not been fully elucidated. In the present study, the embryonic stem (ES) cells-derived cardiomyocytes (ESC-CMs) was employed to investigate PFOS-mediated mechanism in developmental toxicity of cardiomyocytes. Our previous study shows that PFOS induces cardiomyocyte toxicity via causing mitochondrial damage. Nevertheless, the underlying mechanism by which PFOS affects the autophagy-related mitochondrial toxicity in ESC-CMs remains unclear. Here, we found that PFOS induced the swelling of mitochondria and the autophagosome accumulation in ESC-CMs at 40 mu M concentration. PFOS increased the levels of LC3-II, p62, and ubiquitinated proteins. PFOS also induced an increase of LC3 and p62 localization into mitochondria, indicating that mitophagy degradation was impaired. The results of autophagic flux using chloroquine and RFP-GFP-LC3 analysis showed that the accumulation of autophagosome was not caused by the formation but by the impaired degradation. PFOS was capable of blocking the fusion between autophagosome and lysosome. PFOS caused dysfunction of lysosomes because it downregulated Lamp2a and cathepsin D, but it did not induced lysosome membrane permeabilization. Meanwhile, PFOS-mediated lysosomal function and the inhibitory effect of autophagic flux could be reversed by PP242 at 40 nM concentration, an mTOR inhibitor. Furthermore, PP242 restored PFOS-induced ATP depletion and mitochondrial membrane potential. In conclusion, PFOS induced mitochondrial dysfunction via blocking autophagy-lysosome degradation, leading to cardiomyocyte toxicity from ES cells.