Autophagy and the Lysosomal System in Cancer

Abstract

Autophagy and the lysosomal system, together referred to as the autophagolysosomal system, is a cellular quality control network which maintains cellular health and homeostasis by removing cellular waste including protein aggregates, damaged organelles, and invading pathogens. As such, the autophagolysosomal system has roles in a variety of pathophysiological disorders, including cancer, neurological disorders, immune- and inflammation-related diseases, and metabolic alterations, among others. The autophagolysosomal system is controlled by TFEB, a master transcriptional regulator driving the expression of multiple genes, including autophagoly sosomal components. Importantly, Reactive Oxygen Species (ROS) production and control are key aspects of the physiopathological roles of the autophagolysosomal system, and may hold a key for synergistic therapeutic interventions. In this study, we reviewed our current knowledge on the biology and physiopathology of the autophagolysosomal system, and its potential for therapeutic intervention in cancer.

Autophagy as a Therapeutic Target of Natural Products Enhancing Embryo Implantation

“…The fusion of autophagolysosomes with lysosomes is indispensable for the completion of the catabolic process of autophagy [57,58]. Transcription factor EB (TFEB), a member of the MiTF/TFE3 family, has been regarded as a master transcriptional regulator of lysosomal biogenesis [59,60]. The nuclear translocation and transcriptional activity of TFEB are controlled by the phosphorylation of specific serine residues.…”

“…The Ser211 residue is crucial for binding to the 14-3-3 scaffold protein and subsequent cytoplasmic sequestration [62]. The phosphorylation of TFEB is mainly controlled by mTOR kinase and by phosphatase, protein phosphatase 3 catalytic subunit beta (PPP3CB) [59,63]. Other kinases, such as extracellular signal-regulated kinase (ERK), glycogen synthase kinase-3β (GSK3β), and Akt, are also involved in the phosphorylation and cytoplasmic retention of TFEB [60,64,65].…”

“…TFEB translocated into the nucleus regulates the expression of target genes bearing the coordinated lysosomal expression and regulation (CLEAR) motif, thereby participating in the formation and lysosomal fusion of autophagosomes as well as lysosomal biogenesis [57,68]. Thus, TFEB activity has been regarded as a potential target for modulating autophagy and lysosomal function for treating several pathological conditions, including cancer and neurodegenerative diseases [59,69].…”

“…However, to date, only a few studies have focused on the topic of autophagy as a major mechanism underlying the improvement of embryo implantation, and thereby the treatment of female infertility by natural products. In addition, the present autophagy inducers showed limitations due to their low specificity, irregular distribution, and rapid clearance [59]. To encourage the development of novel drug candidates for treating autophagy-related female infertility, the following two strategies might be helpful.…”

“…Formerly, natural product-based autophagy inducers could be structurally modified to enhance efficacy, specificity, bioavailability, and safety [252,253]. Nano-delivery of natural products might be an option to improve aqueous solubility, bioavailability, and distribution to specific tissues [59,254]. Several studies have shown that natural product-loaded nanoparticles, including the autophagy inducers resveratrol, quercetin, and curcumin are promising for the treatment of various diseases such as cancer, inflammation, and arthritis [255].…”