Autophagic cell death exists.
ABSTRACT The term autophagic cell death (ACD) initially referred to cell death with greatly enhanced autophagy, but is increasingly used to imply a death-mediating role of autophagy, as shown by a protective effect of autophagy inhibition. In addition, many authors require that autophagic cell death must not involve apoptosis or necrosis. Adopting these new and restrictive criteria, and emphasizing their own failure to protect human osteosarcoma cells by autophagy inhibition, the authors of a recent Editor's Corner article in this journal argued for the extreme rarity or nonexistence of autophagic cell death. We here maintain that, even with the more stringent recent criteria, autophagic cell death exists in several situations, some of which were ignored by the Editor's Corner authors. We reject their additional criterion that the autophagy in ACD must be the agent of ultimate cell dismantlement. And we argue that rapidly dividing mammalian cells such as cancer cells are not the most likely situation for finding pure ACD.
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ABSTRACT: Autophagy is a tightly regulated intracellular self-digestive process involving the lysosomal degradation of cytoplasmic organelles and proteins. A number of studies have shown that autophagy is dysregulated in cancer initiation and progression, or cancer cells under various stress conditions. As a catabolic pathway conserved among eukaryotes, autophagy is regulated by the autophagy related genes and pathways. MicroRNAs (miRNAs) are small, non-coding endogenous RNAs that may regulate almost every cellular process including autophagy. And autophagy is also involved in the regulation of miRNAs expression and homeostasis. Here we reviewed some literatures on the interaction of miRNAs with autophagy and the application of miRNAs-mediated autophagic networks as a promising target in pre-clinical cancer models. Furthermore, strategies of miRNAs delivery for miRNAs-based anti-cancer therapy will also be summarized and discussed.Cancer Letters 10/2014; · 5.02 Impact Factor
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ABSTRACT: Objective: Neonatal hypoxic-ischemic encephalopathy (HIE) still carries a high burden by its mortality and long term neurological morbidity in survivors. Apart from hypothermia, there is no acknowledged therapy for HIE, reflecting the lack of mechanistic understanding of its pathophysiology. (Macro)autophagy, a physiological intracellular process of lysosomal degradation has been proposed to be excessively activated in excitotoxic conditions such as HIE. The present study examines whether neuronal autophagy in the thalamus of asphyxiated human newborns or P7 rats is enhanced and related to neuronal death processes. Methods: Neuronal autophagy and cell death were evaluated in the thalamus (frequently injured in severe HIE) of both human newborns who died after severe HIE (n=5) and P7 hypoxic-ischemic rats (Rice-Vannuci model). Autophagic (LC3, p62), lysosomal (LAMP1, cathepsins) and cell death (TUNEL, caspase-3) markers were studied by immunohistochemistry in human and rat brain sections, and by additional methods in rats (immunoblotting, histochemistry and electron microscopy). Results: Following severe perinatal asphyxia in both humans and rats, thalamic neurons displayed up to 10-fold (p<0.001) higher numbers of autophagosomes and lysosomes, implying an enhanced autophagic flux. The highly autophagic neurons presented strong features of apoptosis. These findings were confirmed and elucidated in more detail in rats. Interpretation: These results show for the first time that autophagy is enhanced in severe HIE in dying thalamic neurons of human newborns, as in rats. Experimental neuroprotective strategies targeting autophagy could thus be a promising lead to follow for the development of future therapeutic approaches. ANN NEUROL 2014. © 2014 American Neurological Association.Annals of Neurology 08/2014; · 11.91 Impact Factor
- Chemical Reviews 06/2014; · 45.66 Impact Factor
© 2012 Landes Bioscience.
Do not distribute.
in human osteosarcoma cells despite the
testing of as many as 1,400 anticancer
launches a trenchant critique of ACD,
and argues that it may not exist at all. We
think the authors overstate their case,
adopting an unrealistically strict definition
of ACD and neglecting some of the best-
The original definition of ACD was
morphological. The term was introduced
in the 1980s to describe dying cells that
contained numerous autolysosomes and
a few autophagosomes and lacked the
characteristics of other types of cell death.3
The fact that the autolysosomes sometimes
contained most of the cytoplasm and part
of the nucleus, in dying cells showing
no morphological signs of apoptosis or
necrosis, was sometimes argued to imply a
role of autophagy in the death mechanism
(either in cell killing or in cell dismantle-
ment), but this was not part of the
definition.3As recently as 2009, a paper
conformity with some recent usage22,23but
Autophagic cell death exists
Peter G.H. Clarke* and Julien Puyal*
Département de Biologie Cellulaire et de Morphologie; University of Lausanne; Lausanne, Switzerland
Keywords: apoptosis, autophagy, autophagic cell death, cell death, necrosis
The term autophagic cell death (ACD) initially referred to cell death with greatly enhanced autophagy, but is increasingly
used to imply a death-mediating role of autophagy, as shown by a protective effect of autophagy inhibition. In addition,
many authors require that autophagic cell death must not involve apoptosis or necrosis. Adopting these new and
restrictive criteria, and emphasizing their own failure to protect human osteosarcoma cells by autophagy inhibition, the
authors of a recent Editor’s Corner article in this journal argued for the extreme rarity or nonexistence of autophagic cell
death. We here maintain that, even with the more stringent recent criteria, autophagic cell death exists in several
situations, some of which were ignored by the Editor’s Corner authors. We reject their additional criterion that the
autophagy in ACD must be the agent of ultimate cell dismantlement. And we argue that rapidly dividing mammalian
cells such as cancer cells are not the most likely situation for finding pure ACD.
In their Editor’s Corner article “The end
of autophagic cell death?”1
O. Kepp and G. Kroemer deplore the fact
that 486 entries in Medline, almost 7% of
the articles on the subject of autophagy,
refer to autophagic cell death or autophagic
death (henceforth ACD). In light of their
own group’s recent failure to find ACD
summarizing the recommendations of
a cell death nomenclature committee4
favored the initial purely morphological
definition, but a still more recent (2012)
set of recommendations5proposed a func-
tional definition according to which auto-
phagy must not only occur in ACD, but
must mediate the death and be suppressed
by inhibition of the autophagic pathway.
Shen et al. insist that this rarely happens,
but admit that it sometimes does. In fact,
numerous studies report that the blockade
of autophagy (by pharmacological inhibi-
tors, or by RNAi knockdown or condi-
tional knockout or mutation of autophagy
genes) can prevent or delay the death of
cells manifesting enhanced autophagy.6-19
Doubts can be raised about the specificity
of the inhibitors, and the possibility that
autophagy proteins may have additional
functions other than in autophagy,20but
the convergent results from multiple
approaches have convinced most specialists
that autophagy can promote the death of
However, the recent Editor’s Corner
article goes beyond the new recommenda-
tions, in requiring two additional criteria.
The first of these may have merits, but the
second seems to us excessive.
The first of these additional criteria, in
not all,21is that ACD must be a distinct
death mechanism, independent of apoptosis
or necrosis. Thus, situations where auto-
phagy triggers apoptosis14,17,24,25or necro-
sis, or occurs in parallel with them, are
excluded even when the autophagy has
been clearly shown to promote cell death.
This criterion was recommended in a
recent critical review in this journal by
H.-M. Shen and P. Codogno,8except that
the definition of necrosis was widened to
include autophagic cell death, and the
conclusion was that, even with this strict
definition, ACD does exist in several
situations (they cited approximately ten).
Shen and Codogno argued that the phy-
siological role of ACD (e.g., in develop-
ment) may be limited mainly to lower
that it occurred even in mammalian cells
in artificial situations, including hippo-
campal neural stem cells following insulin
withdrawal.12The Editor’s Corner authors
admit that ACD (even in this restricted
sense) may be involved in “model organ-
isms such as Drosophila,” but cite only
one case, and focus their discussion on
mammalian cells, especially cancer cells.
They seem to be unconcerned by the fact
that the research on what they call “model
organisms” is sufficient to prove the
existence of ACD.
*Correspondence to: Peter G.H. Clarke or Julien Puyal; Email: firstname.lastname@example.org or JulienPierre.Puyal@unil.ch
Submitted: 03/27/12; Revised: 04/11/12; Accepted: 04/13/12
Autophagy 8:6, 867–869; June 2012;G2012 Landes Bioscience
© 2012 Landes Bioscience.
Do not distribute.
death execution and cell destruction apart
from apoptosis and necrosis. Wholesale
cell dismantlement is indeed a possibility,
as one of us once suggested.3Alternatively,
that pure, nonapoptotic ACD may be
But they also introduce a second
definitional criterion, which appears to us
excessive. It maintains that for cell death to
be ACD the autophagy must “…be itself
responsible for the final dismantling of
cellular content and hence execute a lethal
pathway” (legend of their Fig. 2). We
think the “final dismantling of cellular
content” would be not so much lethal as
postlethal, and it seems arbitrarily restric-
tive to require that ACD fulfill both this
criterion and the criterion that inhibition
of autophagy must protect. It is reasonable
to postulate a role of autophagy either in
the induction of cell death or in the final
dismantlement of cells, but not to require
both in the same cell. In the former case,
survival, in the latter it might delay the
clearance of cell debris,27,28but would
hardly be expected to promote survival.
It would be a remarkable coincidence if
autophagy played both roles in a single
We do, however, appreciate that the
Editor’s Corner authors required that
ACD involve a role of autophagy in cell
dismantlement because there is no cur-
rently accepted alternative mechanism of
autophagy might initiate some other
mechanism that is currently unknown.
Its clarification might one day justify a
change in terminology, but for the moment
we need the term ACD. The abundance of
detection protocols for apoptosis probably
causes its prevalence to be overestimated as
compared with ACD (and also to necrosis).
Abandoning the term would exacerbate
this problem and the imposition of restric-
tive theory-laden nomenclature
inhibit some scientists from making dis-
coveries that would refute current opinion.
Finally, it may be inappropriate to use
mammalian cancer cells as a test case for
the existence of ACD, for three reasons.
First, pure cases of ACD seem to be
relatively rare in mammals. A review of cell
death in development covering the litera-
ture up to 1989 concluded that ACD
(morphologically defined) was the pre-
dominant type of cell death in meta-
morphosing insects and amphibians, but
found only one case in mammals;3and
more recent evidence indicates that, even
though autophagy does contribute to cell
death in mammals,7,8,14this often involves
a complex interaction between multiple
death pathways rather than pure ACD.8,22
Second, dividing and recently postmitotic
cells tend to be so sensitive to apoptosis
unable to occur in most cases. For
example, studies on neurons indicate
that it takes several days of postmitotic
development before the autophagic death
mechanism begins to predominate over
the apoptotic one.29Third, cancer cell
lines are hardly representative of what
happens in normal animals, and they
have multiple mutations, so that death-
mediating functions of autophagy might
be selected against. For these three reasons,
even though ACD probably does occur in
mammalian cancer cells,23focusing on
them may give an exaggerated impression
of its rarity.
In conclusion, even with the recent
tendency to include death promotion by
autophagy and independence from apop-
tosis and necrosis in the definition of
ACD, it does occur. The additional
requirement of Shen et al. that ACD must
involve a role for autophagy in cell
dismantlement seems excessive. And mam-
malian cancer cells may not provide a good
model for testing whether ACD exists.
The research of J.P. is supported by grant
310030-130769 from the Swiss National
Science Foundation and by grants from
the fondation Emma Muschamp and from
the Faculté de Biologie et de Médecine
(University of Lausanne).
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