Autophagy in disease: a double-edged sword with therapeutic potential

Abstract

Autophagy is a catabolic trafficking pathway for bulk destruction and turnover of long-lived proteins and organelles via regulated lysosomal degradation. In eukaryotic cells, autophagy occurs constitutively at low levels to perform housekeeping functions, such as the destruction of dysfunctional organelles. Up-regulation occurs in the presence of external stressors (e.g. starvation, hormonal imbalance and oxidative stress) and internal needs (e.g. removal of protein aggregates), suggesting that the process is an important survival mechanism. However, the occurrence of autophagic structures in dying cells of different organisms has led to the hypothesis that autophagy may also have a causative role in stress-induced cell death. The identification within the last decade of a full set of genes essential for autophagy in yeast, the discovery of human orthologues and the definition of signalling pathways regulating autophagy have accelerated our molecular understanding and interest in this fundamental process. A growing body of evidence indicates that autophagy is associated with heart disease, cancer and a number of neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's diseases. Furthermore, it has been demonstrated that autophagy plays a role in embryogenesis, aging and immunity. Recently, it has been shown that autophagy can be intensified by specific drugs. The pharmacological modulation of the autophagic pathway represents a major challenge for clinicians to treat human disease.

Immunohistochemical analysis of macroautophagy

“…[23][24][25] Considering the potential therapeutic implications of the pharmacological modulation of autophagy in many of these pathological conditions, the development of a fast and simple detection method for autophagy in clinical tissue samples has become a major priority. Increasing evidence suggests that immunohistochemical staining of LC3 could be a valuable technique for evaluation of autophagy in situ, particularly in the field of cancer.…”

ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy

“…Like autophagy, CMA is also stimulated by cellular stressors like starvation and oxidative stress. 91,92 It is thought that these autophagy pathways may not have a redundant function since autophagy would be involved in the (nonspecific) removal of ROS-damaged organelles and protein aggregates, 40,45,93 typically formed after oxidative damage to proteins, whereas CMA would remove soluble oxidatively damaged proteins. 94 The suitability of CMA for the removal of oxidized proteins has been hypothesized to involve the creation of novel KFERQ-like motifs due to oxidative amino acid modification.…”

“…Studies performed in cultured mammalian cells responding to a variety of insults eventually leading to cell death, support the view that autophagy stimulation in dying cells represents an attempt to alleviate the stress rather than amplifying it. 44 Thus blockage of autophagy by means of RNAi-mediated knockdown of essential autophagy genes interferes with the clearance of toxic aggregateprone proteins in neuronal cells, 40,45 hepatocytes, 46 and in a variety of physiopathological conditions linked to ER stress, 47 ultimately resulting in an enhancement of cell death. Studies focusing on the role of autophagy in cancer propagation and in response to therapy, which is the focus of paragraph Autophagy, ROS and cancer: A two-faced story, also define autophagy stimulation as a crucial adaptation mechanism in the face of chronic metabolic stress during carcinogenesis or acute cellular injury in response to a variety of therapeutic drugs.…”

“…Furthermore, autophagy plays a role in development, aging and immunity, and a growing body of evidence indicates its role in the etiology of different pathologies including heart disease, cancer and neurodegeneration. 40,41 Autophagy as a survival signal. In the mammalian system, loss-of-function of autophagy genes points to a role of autophagy as a cytoprotective mechanism facilitating the removal of dying cells.…”

TNFα-Induced Necroptosis and Autophagy via Supression of the p38–NF-κB Survival Pathway in L929 Cells

“…However, under certain environmental conditions, autophagy can also be a contributor to programmed cell death (8,9). Three main types of autophagy have been identified: macroautophagy, microautophagy, and chaperone-mediated autophagy.…”