|Macroautophagy (hereafter referred to as autophagy) is a complex,
multi-step process normally involved in regulated turnover of longlived
proteins and damaged organelles. Autophagy is a form of cellular
self digestion in which cellular constituents are engulfed in doublemembrane
containing autophagosomes. Their vesicular content is subsequently
digested by lysosomal proteases after fusion of autophagosomes
with lysosomes. In recent years, elucidation of the physiological
and pathophysiological aspects of autophagy and the identification of
key components of the autophagy interacting network has generated a
tremendous interest in the concept of exploiting autophagy for cancer
|What is the common rationale of targeting autophagy for cancer
therapy? The net effects of autophagy on cell death/cell survival decisions
are highly dependent of the cellular context and hence autophagy
may have dual, opposing roles . It is now widely accepted that autophagy
primarily constitutes a quality control mechanism and a prosurvival
stress response, e.g. under conditions of nutrient deprivation,
organelle damage, oxidative stress or after DNA damage . In line
with this hypothesis, there are numerous examples and experimental
paradigms where pharmacological inhibition or genetic ablation of
pro-survival autophagy can sensitize cancer cells to various types of
therapy [7,8]. On the other hand, there is also evidence supporting the
notion that enforced over activation of autophagy can lead to “autophagic
cell death” (type II cell death), i.e. massive cellular self digestion via
the autophagosomal-lysosomal pathway beyond the point allowing cell
survival. This could be especially relevant in apoptosis-resistant cells
such as gliobastoma cells, where autophagy may act as a backup cell
death mechanism executing a non-apoptotic, alternative death program
|However, this is a controversial, hotly debated issue [11,12] and
the very existence of autophagic cell death has been challenged recently
. Indeed, in many paradigms of cell death associated with induction
of autophagy, autophagy may just act as a bystander without a
direct role in the death process. In line with this notion, many of the
past studies on “autophagic cell death” did not really investigate the
pro-death function of autophagy and therefore do not fulfil the current,
more stringent criteria that recently were suggested to be applied for
autophagy-dependent cell death [5,11].
|Despite this ongoing controversy regarding the pro-death role of
autophagy, there are a number of experimental studies suggesting that
pro-autophagic drugs may elicit an autophagy-dependent cell death in
certain cases . In addition to these findings on drug-induced autophagic
cell death in mammalian cells, there is also considerable evidence
for autophagy-dependent developmental cell death in Drosophila
[14,15]. Therefore, the issue of autophagy as a cell death mechanism in
general and the ensuing therapeutic consequences for cancer therapy
warrant further examination in order to determine whether activation
of autophagy may indeed have significance for therapy, especially in
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