Abstract
Autophagy has important functions in maintaining energy metabolism under conditions of starvation and to alleviate stress by removal of damaged and potentially harmful cellular components. Therefore, autophagy represents a pro-survival stress response in the majority of cases. However, the role of autophagy in cell survival and cell death decisions is highly dependent on its extent, duration, and on the respective cellular context. An alternative pro-death function of autophagy has been consistently observed in different settings, in particular, in developmental cell death of lower organisms and in drug-induced cancer cell death. This cell death is referred to as autophagic cell death (ACD) or autophagy-dependent cell death (ADCD), a type of cellular demise that may act as a backup cell death program in apoptosis-deficient tumors. This pro-death function of autophagy may be exerted either via non-selective bulk autophagy or excessive (lethal) removal of mitochondria via selective mitophagy, opening new avenues for the therapeutic exploitation of autophagy/mitophagy in cancer treatment.
Highlights
Autophagy in Cell Survival and Cell Death. One such apoptosis-independent cell death mechanism relies on the over activation of autophagy, a cellular stress response that normally serves as a quality control mechanism
Similar threshold effects the other hand, there is conclusive evidence that prolonged over activation of the on cell survival vs cell death are commonly observed in various stress responses like the endoplasmatic autophagosomal/lysosomal pathway can lead to autophagic cell death (ACD, type II cell death)
The net effect of autophagy on cell survival is highly dependent on its intensity and Recently, ACD was further defined by the Nomenclature Committee on Cell Death (NCCD) based duration, and on its particular context (Figure 2)
Summary
In order to remove damaged or unwanted cells, multicellular organisms rely on multiple forms of programmed cell death (PCD). PCD is an evolutionarily-conserved phenomenon and the most common and best-studied form of PCD is apoptosis (type I cell death) [1]. Multiple alternative cell death programs have been described in the last decades [2,3]. Apoptotic cell death is believed to be the main mode-of-action of most conventional chemotherapeutics and radiation therapy in tumor treatment. Many cancers are highly resistant to apoptosis and numerous studies illustrate that alternative, non-apoptotic forms of PCD [2,4]. Exist, some of which might represent suitable therapeutic avenues, in particular, for the treatment of apoptosis-refractory cancers
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