Autophagy in tumor suppression and cancer therapy

Abstract

Autophagy is a stress-induced cell survival program whereby cells under metabolic, proteotoxic, or other stress remove dysfunctional organelles and/or misfolded/polyubiquitylated proteins by shuttling them via specialized structures called autophagosomes to the lysosome for degradation. The end result is the release of free amino acids and metabolites for use in cell survival. For tumor cells, autophagy is a double-edged sword: autophagy genes are frequently mono-allelically deleted, silenced, or mutated in human tumors, resulting in an environment of increased oxidative stress that is conducive to DNA damage, genomic instability, and tumor progression. As such, autophagy is tumor suppressive. In contrast, it is important to note that although tumor cells have reduced levels of autophagy, they do not eliminate this pathway completely. Furthermore, the exposure of tumor cells to an environment of increased metabolic and other stresses renders them reliant on basal autophagy for survival. Therefore, autophagy inhibition is an active avenue for the identification of novel anti-cancer therapies. Not surprisingly, the field of autophagy and cancer has experienced an explosion of research in the past 10 years. This review covers the basic mechanisms of autophagy, discusses its role in tumor suppression and cancer therapy, and posits emerging questions for the future.

Target of Rapamycin (TOR) and Autophagy in Chronic Hepatitis C Virus Infection: Relation to Disease Activity

“…The role of autophagy in hepato -carcinogenesis remains controversial. Dual effects of autophagy in cancer have been proposed depending on the tumor microenvironment [25,91]. Autophagy may function as a tumor suppressor through removal of damaged and senescent mitochondria and thus, restricts oxidative and metabolic stress and limits genetic instability and oncogenic mutations [25,92].…”

“…Dual effects of autophagy in cancer have been proposed depending on the tumor microenvironment [25,91]. Autophagy may function as a tumor suppressor through removal of damaged and senescent mitochondria and thus, restricts oxidative and metabolic stress and limits genetic instability and oncogenic mutations [25,92]. On the other hand, mounting evidence suggests that autophagy may have cancer promoting effect [91] through providing stress tolerance, and inhibition of apoptosis [93].…”

“…It is likely that dysregulation of the mTOR-autophagy pathway may contribute too many human disorders including viral infections [22]. Inflammatory disorders [23,24] and cancer [25,26] and could be an attractive avenue for future therapeutic approaches [16]. The aim of the present work was to study the role of mTOR and autophagy in the progression of HCV-related liver disease.…”

Signalling mechanisms that regulate metabolic profile and autophagy of acute myeloid leukaemia cells

“…Macroautophagy, hereafter referred as to autophagy, is a multi‐step self‐degradative process by which cytoplasmic content, such as long‐lived proteins and superfluous/damaged organelles, is delivered to lysosomes for degradation 31. Deregulation of autophagy has been extensively described in AML acting both as tumour promoting and suppressing 26, 32, 33, 34. Therefore, the elucidation of the interconnection between the nutrient‐sensing players, autophagy and energetic metabolism is of major relevance to understand cellular homeostasis and survival of AML cells.…”

Effect of glutamate on autophagy induced by energy stress in SH-SY5Y neurons

“…Tokom procesa sazrevanja citoplazmatski sadržaj se pakuje u autofagozom. Kada je stvaranje autofagozoma završeno on se spaja sa lizozomom, stvarajući autofagolizozom u kome se vrši digestija makromolekulskog sadržaja (7)(8)(9)(10)(11). Kod sisara je prepoznavanje citoplazmatskog sadržaja, koji se selektivno pakuje u autofagozom, posredovano adaptorskim proteinima kao što su p62 (engl.…”