Cell Biology International ISSN 1065-6995

doi: 10.1002/cbin.11137

REVIEW

Cell death: a review of the major forms of apoptosis, necrosis

and autophagy
Mark S D’Arcy*
Hertfordshire International College (HIC), Collage Lane, Hatfield, AL10 9AB, UK

Abstract
Cell death was once believed to be the result of one of two distinct processes, apoptosis (also known as programmed cell
death) or necrosis (uncontrolled cell death); in recent years, however, several other forms of cell death have been discovered
highlighting that a cell can die via a number of differing pathways. Apoptosis is characterised by a number of characteristic
morphological changes in the structure of the cell, together with a number of enzyme‐dependent biochemical processes.
The result being the clearance of cells from the body, with minimal damage to surrounding tissues. Necrosis, however, is
generally characterised to be the uncontrolled death of the cell, usually following a severe insult, resulting in spillage of the
contents of the cell into surrounding tissues and subsequent damage thereof. Failure of apoptosis and the resultant
accumulation of damaged cells in the body can result in various forms of cancer. An understanding of the pathways is
therefore important in developing efficient chemotherapeutics. It has recently become clear that there exists a number of
subtypes of apoptosis and that there is an overlap between apoptosis, necrosis and autophagy. The goal of this review is to
provide a general overview of the current knowledge relating to the various forms of cell death, including apoptosis,
necrosis, oncosis, pyroptosis and autophagy. This will provide researchers with a summary of the major forms of cell death
and allow them to compare and contrast between them.

Keywords: apoptosis; autophagy; cancer; cell differentiation; pyroptosis; necroptosis; necrosis

Introduction proliferation can result in the development of diseases such

as cancer that can result in death of the organism, whereas
In multi‐cellular organisms, there is a constant effort to
an excessive level of cell death can result in diseases such as
maintain a homoeostatic balance between the number of
Alzheimer’s, Parkinson’s or rheumatoid arthritis.
new cells that are generated via mitosis and the number of
Although there is a large and complex web of interacting
damaged or unrequired cells that are removed from the
gene products involved in the cell cycle and cell death, from
body. This constant turnover of cells is necessary for the
the 1990s onwards, certain receptors, enzymes and
development of structures such as the fingers and toes,
regulatory proteins have emerged as key regulators in
which arise from the initially webbed limbs found in the
these processes. These regulators when abnormally ex-
human foetus (Zakeri and Ahuja, 1997). The mechanisms
pressed or when mutated can have a direct effect on the
by which animals regulate mitosis, detect cellular abnorm-
machinery of the cell cycle, with some, for example, the
alities and initiate the method of programmed cell death
Bcl‐2 family of enzymes (Czabotar et al., 2013) and
known as apoptosis (Soengas et al., 1999) involves a large
transglutaminase 2 (Budillon et al., 2013) either stimulating
number of regulatory genes. Some of these regulatory genes
apoptosis or inhibiting it depending on their expression
act to stimulate mitosis, whilst others inhibit mitosis or
profile, localisation or conformation. The inhibition of
initiate apoptosis or other forms of programmed cell death
apoptosis or other mechanisms of controlled cell death can
such as pyroptosis or autophagy. Uncontrolled cellular
directly influence the susceptibility of a cancer to

*Corresponding author: e‐mail: mada@learning.hibt-uk.co.uk

Abbreviations: AML, acute myeloid leukaemia; APAF1, adaptor protein apoptotic protease activating factor 1; CARD, caspase recruitment domain;
DISC, death‐inducing signal complex; DR, death receptor; FADD, FAS‐associated death domain; LAMP, lysosomal receptor; MHC, major
histocompatibility complex; MLKL, mixed lineage kinase; MPT, mitochondrial permeability transition; RIP, receptor‐interacting proteins; TRADD,
tumour necrosis factor receptor‐associated death domain

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Mark S D’Arcy
chemotherapeutic drugs, in many cases, resulting in drug
resistance. Increased transglutaminase 2 expression has ,for
example, been implicated with a poor prognosis in acute
myeloid leukaemia (AML) and it has been observed
(Lancelot et al., 2013) that elevated levels of transglutami-
nase 2 expression are found in patients during an AML
relapse as compared with the initial levels when first
diagnosed.
The body of knowledge in the field of cancer biology is
increasing at an ever faster rate since early studies into cell
signalling and programmed cell death in the 1980s;
particularly with regards to the involvement of the cell
cycle and apoptosis as regulators of both the severity and
susceptibility to drugs of cancers. For example, it has
recently become apparent (Seehawer et al., 2018) that the
tissue microenvironment found around cells undergoing
necroptosis directs lineage commitment in liver cancer,
showing that the type of cell death present in a particular
tissue can effect tumorgenesis.
Cell death in brief
In order to develop effective treatments for cancer and
other diseases characterised by abnormalities in the
regulation of cell death, an understanding of the differing
ways that cells can lose viability and eventually die is
necessary. The differing mechanisms of cell death will be
overviewed in the proceeding sections, however, broadly
speaking, cells are removed from the tissue in either a
controlled (programmed) manner involving a series of
biochemical and molecular events or alternatively in a
poorly controlled manner, resulting in the spilling of the
cellular contents into surrounding tissues (Kerr et al.,
1972). The most well characterised and prevalent form of
controlled cell death is termed ‘apoptosis’ from the Greek
denoting ‘falling off’ as in the leaves falling from a tree,
whilst the uncontrolled form of cell death is usually
referred to as ‘necrosis’ from the Greek denoting ‘to kill’.
Overview of apoptosis
The word apoptosis was first used in a 1972 paper by Kerr,
Wyllie, and Currie to describe a morphologically distinct
type of cell death (Kerr et al., 1972). Apoptosis is the
process by which a cell ceases to grow and divide and
instead enters a process that ultimately results in the
controlled death of the cell without spillage of its contents
into the surrounding environment. Apoptosis is also
sometimes referred to as programmed cell death (or
more colloquially ‘cellular suicide’). The initiation of
apoptosis is dependent on the activation of a series of
cysteine‐aspartic proteases known as caspases. There are
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A review of the major forms of cell death
two categories of caspases, the initiator caspases and
the executioner caspases (Elmore, 2007). Once cell damage
is detected, the initiator caspases (caspases 8 and 9)
are activated from inactive procaspases and go on to
activate the executioner caspases (caspases 3, 6 and 7). The
activation of the executioner caspases initiates a cascade of
events that results in DNA fragmentation from activation
of endonucleases, destruction of the nuclear proteins and
cytoskeleton, crosslinking of proteins, the expression of
ligands for phagocytic cells and the formation of apoptotic
bodies (Martinvalet et al., 2005; Poon et al., 2014). Broadly
speaking, apoptosis (Figure 1) can be distinguished from
the unprogrammed form of cell death—necrosis (see
Figure 2), both visually under the microscope and via a
number of molecular biology techniques; including flow
cytometry with Annexin V‐FITC staining and DNA
fragmentation assays. In apoptosis, the apoptotic bodies
containing the contents of the dead cell can be phagocy-
tosed by the surrounding cells, although this behaviour is
observed primarily in cell culture (Elmore, 2007), in vivo
cells such as macrophages often remove apoptotic cells
before they fragment. This results in a containment of the
injured tissue, and as a result, reduces the risk of collateral
damage to surrounding cells.
The process of apoptosis is highly conserved within
multi‐cellular organisms and is genetically controlled
(Lockshin and Zakeri, 2004). Apoptosis can be initiated
by the cell itself when it detects damage via a number of
intracellular sensors; a mechanism known as the intrinsic
pathway. Alternatively, it can result from the interaction
between a cell of the immune system and a damaged cell,
which is known as the extrinsic pathway of apoptosis (Sica
et al., 1990; Oppenheim et al., 2001). In the human body, it
is estimated that approximately 1 × 109 cells undergo
apoptosis per day (Elliott and Ravichandran, 2010). Both
the intrinsic and extrinsic pathways of apoptosis work
synergistically to ensure that multi‐cellular organisms
remain healthy and defective cells are removed from the
body. Failure to regulate apoptosis can result in the
pathologies exhibited in many diseases. For example, in
degenerative diseases such as Alzheimer’s where neuronal
death appears to be initiated by the activation of caspases, a
key group of enzymes are involved in apoptosis (Dickson,
2004). Too little apoptosis, however, can result in the
uncontrolled growth and division of cells that is observed
in cancer. See Figure 1 for a summary of the intrinsic and
extrinsic pathways of apoptosis.
Intrinsic pathway of apoptosis
The intrinsic pathway, also known as the mitochondrial
pathway of apoptosis (Igney and Krammer, 2002) involves
a variety of stimuli that act on multiple targets within the
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Figure 1 A summary of the major components of the intrinsic and extrinsic pathways of apoptosis. The intrinsic pathway of apoptosis is
initiated by the cell itself in response to damage. The extrinsic pathway is initiated via death receptors stimulated by cells of the immune system. Both
pathways converge when caspase 3 (executioner caspase) is activated, resulting in cell death.

Figure 2 Summary of the pathways associated with pyroptosis. Pyroptosis is initiated in response to infection of the cell from bacteria such as
Salmonella or Shigella. Ionic leakage occurs via pores in the plasma membrane, the formation of which is triggered by caspase 1 and the result of
which is lysis of the cell. Caspase 1 also triggers the release of the inflammatory cytokines IL‐1β and IL‐18 into the surrounding tissue. IL, interleukin.

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Mark S D’Arcy
cell. This form of apoptosis is dependent on factors released
from the mitochondria and is initiated either from a
positive or negative pathway. Negative signals arise from
the absence of cytokines, hormones and growth factors in
the immediate environment of the cell. Without these pro‐
survival signals, pro‐apoptotic molecules within the cell,
such as puma, noxa and bax that are normally inhibited
become active and initiate apoptosis. Other factors that
initiate apoptosis are positive in nature and include
exposure to hypoxia, toxins, radiation, reactive oxygen
species, viruses and a variety of toxic agents (Brenner and
Mak, 2009), although in the case of some cells, such as
neutrophils, hypoxia can promote cell survival (Walmsley
et al., 2005).
The initiator caspase that controls the intrinsic pathway
of apoptosis is caspase 9, which is able to bind to adapter
protein apoptotic protease activating factor 1 (APAF1)
following exposure of its caspase recruitment domain
(CARD domain). APAF1 in a non‐apoptotic cell is usually
folded in such a manner that its CARD domain is blocked
and procaspase 9, which also contains a CARD domain is
unable to bind to it. When apoptosis is induced either by
positive or negative stimuli, changes are triggered in the
mitochondrial membrane, the result of which is the
opening of the mitochondrial permeability transition
(MPT) pore. Once the MPT pore is open, pro‐apoptotic
proteins (including cytochrome c, Smac/Diablo and HtrA2/
Omi) are able to leak from the mitochondria into the
cytoplasm and activate apoptosis (Cain et al., 2002).
Cytochrome c induces apoptosis by binding to the WD
domain of APAF1 monomers, which results in a con-
formational change in APAF1 exposing a nucleotide
binding and oligomerization domain that is able to bind
deoxy ATP (dATP). This binding induces an additional
conformational change in APAF1, exposing both its CARD
and oligomerization domains, thus allowing several
APAF1s to assemble into a complex known as an
apoptosome (Acehan et al., 2002). The apoptosome
contains in its open centre several exposed CARD domains,
which then recruit and activate several procaspase 9
proteins. These activated caspase 9 enzymes are able to
activate the executioner procaspase 3, which in the form of
active caspase 3 can fully induce apoptosis (Cain et al.,
2002). Smac/Diablo and HtrA2/Omi help initiate apoptosis
by inhibiting inhibitors of apoptosis proteins (IAPs),
although without the release of cytochrome c, inhibiting
IAPs alone is insufficient to initiate apoptosis (Ekert and
Vaux, 2005).
Extrinsic pathway of apoptosis
The extrinsic pathway, also known as the death receptor
(DR) pathway of apoptosis (Igney and Krammer, 2002) is
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A review of the major forms of cell death
initiated by patrolling natural killer cells or macrophages
when they produce death ligands, which upon binding with
DRs in the target cell membrane induce the extrinsic
pathway via the activation of procaspase 8 to caspase 8
(Kim et al., 2004). DRs are members of the tumour necrosis
factor (TNF) superfamily and include several members,
(Bossen et al., 2006) with each DR having a corresponding
death ligand (see Table 1). To activate caspase 8, a death
ligand must bind to a DR, resulting in recruitment of
monomeric procaspase 8 via its death‐inducing (DED)
domain to a death‐inducing signal complex (DISC) located
on the cytoplasmic domain of the ligand‐bound DR. The
DISC also includes either an adaptor protein known as the
FAS‐associated death domain (FADD) or TNF receptor
(TNFR)‐associated death domain (TRADD), which facil-
itates the interaction of procaspase 8 to the DISC (Kim
et al., 2004). The recruitment of several procaspase 8
monomers to the DISC results in their dimerisation and
activation, with the resultant caspase 8 able to induce
apoptosis via one or the other of two distinct sub‐pathways.
The particular sub‐pathway that is induced depends on
whether the cells are classed as type I or type II cells
(Samraj et al., 2006). In type I cells, caspase 8 directly
cleaves executioner caspases and therefore directly initiates
apoptosis. In type II cells, IAPs inhibit direct caspase 8
activation of the executioner caspases, unless the IAPs are
inhibited by proteins released from the mitochondria
(Spencer et al., 2009). The important role of caspase 8 in
controlling the extrinsic pathway of apoptosis (see Figure
1) has been observed in caspase 8 deficient mice, which
show no response to DR ligands (Varfolomeev et al., 1998).
Whether or not apoptosis is triggered by the intrinsic or
the extrinsic pathways, its tight regulation is essential and
failure to regulate it effectively can have dire consequences.
In cancer, for example, the cell fails to initiate apoptosis
due to mutations in the various mechanisms of initiation. If
this occurs in tandem with the cell failing to respond to
external signals, that would normally provoke the extrinsic
Table 1 Human death receptors and their corresponding
ligands.
Death receptor (DR) Death ligand
TNF receptor 1 (TNFR1) TNF
CD95 (also known as Fas and CD95‐ligand (CD95‐L, also
APO‐1) known as Fas‐ L)
Death receptor 3 (DR3) TLIA
TNF‐related apoptosis‐inducing TRAIL (also known as Apo2‐L)
ligand receptor 1 (TRAIL‐R1,
also known as DR4)
TNF‐related apoptosis‐inducing TRAIL (also known as Apo2‐L)
ligand receptor 1 (TRAIL‐R2,
also known as DR4)
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pathway or inhibit proliferation, then this causes the cell to
grow and divide uncontrollably, resulting in the formation
of either a benign tumour or in cancer (Philchenkov
et al., 2004).
Pyroptosis: programmed cell death with collateral
damage
Classic apoptosis (both the intrinsic and extrinsic path-
ways) are characterised by the compartmentalisation of
intracellular components of the cell and removal of cellular
debris without any collateral damage occurring to
surrounding tissues. An alternative form of apoptosis has
been identified (Boise and Collins, 2001) that although
following a programmed series of caspase‐dependent
events, is pro‐inflammatory. This form of cell death termed
‘pyroptosis’ (Fink and Cookson, 2005) has been identified
in macrophages infected with Salmonella or Shigella and is
not observed in caspase 1‐deficient cells (Li et al., 1995).
Once activated by a pathogen, caspase 1 processes the pro‐
forms of the inflammatory cytokines interleukin 1β (IL‐1β)
and IL‐18 into their active forms, resulting in apoptosis of
the cell, but with a concurrent release of inflammatory
cytokines into the surrounding environment (Hersh et al.,
1999). Procaspase 1 cleavage into active caspase 1 results in
the formation of plasma membrane pores. The pores allow
the flow of ions, resulting in the equalisation of the usual
ionic gradient between the intracellular and extracellular
environment; water then enters the cell, resulting in
swelling and lysis. In pyroptosis, unlike in apoptosis,
nuclear integrity is maintained (no fragmentation)
although nuclear condensation is observed (Hersh
et al., 1999).
Since its discovery, pyroptosis has been observed in the
central nervous system (Liu et al., 1999) and the
cardiovascular system (Kolodgie et al., 2000), suggesting
that this form of cell death is biologically significant. See
Figure 2 for an overview of pyroptosis.
Autophagy: a mechanism for both protecting and
killing stressed cells
Autophagy is a process where cellular components such as
macroproteins or even whole organelles are sequestered
into lysosomes for degradation (Shintani and Klionsky,
2004, Mizushima et al., 2008). The lysosomes are then able
to digest these substrates, the components of which can
either be recycled to create new cellular structures and/or
organelles or alternatively can be further processed and
used as a source of energy. Autophagy can be initiated by a
variety of stressors, most notably by nutrient deprivation
(caloric restriction) or can result from signals present
during cellular differentiation and embryogenesis and on
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Mark S D’Arcy
the surface of damaged organelles (Mizushima et al., 2008).
Autophagy has also been shown to be involved in both the
adaptive and the innate immune system where it may
degrade intracellular pathogens and deliver antigens to
MHC class II holding compartments and initiate the
transportation of viral nucleic acids to Toll‐like receptors
(Levine and Deretic, 2007). Although autophagy is often
used to recycle cellular components, it can result in
destruction of the cell and in this way has been linked to
removal of senescent cells from aged tissues and destruc-
tion of neoplastic lesions (Mizushima et al., 2008). Failure
of autophagy as well as potentially allowing the develop-
ment of cancer has also been associated (particularly in
aged organisms) with the accumulation of protein aggre-
gates in the neurons and the development of neurodegen-
erative conditions including Alzheimer’s disease (Nixon
and Yang, 2011).
To date, three distinct forms of autophagy have been
identified—macroautophagy, microautophagy and selective
autophagy (Cuervo, 2004). In the most described form of
autophagy ‘macroautophagy’, whole regions of the cell are
enclosed in double‐membrane vesicles referred to as
autophagosomes. These autophagosomes then fuse with
lysosomes to become autophagolysosomes and the contents
are then degraded by proteases present therein. In
microautophagy, the cargo (organelles or regions of the
cytosol) directly interact with and fuse with the lysosomes
(Li et al., 2012a, b). Microautophagy is more specific than
macroautophagy and can be triggered by signalling
molecules present on the surface of damaged organelles
such as mitochondria or peroxisomes resulting in specific
fusion of lysosomes with these organelles. Depending on
which organelle is targeted, the resultant autophagic vesicle
is referred to by a specific name, for example, if a
mitochondria, the term used is mitophagy or for a
peroxisome, the term peroxophagy is used. In selective
autophagy, also known as chaperone‐mediated autophagy,
proteins within the cytoplasm are targeted for fusion with
lysosomes by a cytosolic chaperone through interaction
between the chaperone and a pentapeptide present within
the amino acid sequence of the substrate. Substrate proteins
then bind to a lysosomal receptor LAMP‐2A and are
carried into the lysosome for degradation (Dice, 2007).
Figure 3 provides an overview of the general mechanism of
autophagy. The specific steps of autophagy are as follows.
Initially, autophagy is mediated by the ULK1 complex. In
order to form a phagophore, a class III phosphoinositide 3‐
kinase (P13K) complex also is required. This complex
consists of 5 sub‐units (ATG14L, Beclin 1, VSP34 and
VSP15). A complex composed of ATG5, ATG12 and
ATG16L, together with lipidated microtubule‐associated
protein light chain 3 (LC3II) stimulates the elongation of
the phagophore and is essential for the autophagosome to
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Figure 3 A summary of the steps involved in autophagy. Autophagy results from the formation of a phagophore, initiated by the ULK1 and the
ATG5‐ATG12‐ATG16L complexes. They then close around ubiquitinised proteins bound to p60 and LC3II. The phagophore then closes to form an
autophagosome, which then fuses with a lysosome resulting in the degradation of the contents.
form. The protein p60 binds to any ubiquitinated proteins
and they are thus targeted for degradation. P60 binds to
LC3II as the autophagosome is formed and the target
proteins and organelles become engulfed in the newly
formed autophagosome. The autophagosome then fuses
with the lysosome and the contents are digested (Ndoye
and Weeraratna, 2016).
Necrosis: cell death with collateral damage
Unlike apoptosis, necrosis is an alternative uncontrolled
form of cell death that is induced by external injury, such as
hypoxia or inflammation (Elmore, 2007). This process
often involves upregulation of various pro‐inflammatory
proteins and compounds, such as nuclear factor‐κB,
resulting in the rupture of the cell membrane causing
spillage of the cell contents into surrounding areas,
resulting in a cascade of inflammation and tissue damage.
In contrast to apoptosis, necrosis is an energy independent
form of cell death, where the cell is damaged so severely by
a sudden shock (radiation, heat, chemicals, hypoxia, etc.)
that it is unable to function. The cell usually responds by
swelling, (a process known as oncosis) as it fails to maintain
homoeostasis with its environment. This definition of
necrosis as a counterpoint to apoptosis is a useful concept,
however, as necrosis is usually observed as an endpoint
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state in cell culture by the presence of cellular fragments in
the media, what is described in many cases in a cell culture
setting as necrosis is often simply the remains of late
apoptotic cells, the apoptotic bodies of which have lost
integrity. In vivo these apoptotic bodies would be
phagocytosed by patrolling white blood cells, however, in
the single cell population environments found in cul-
ture this does not occur, which can confuse the diagnosis of
the exact mechanism of cell death. A more accurate
counterpoint to controlled cell death is oncosis. Both
oncosis and its progression to necrosis is illustrated in
Figure 5, following a discussion of oncosis.
Necroptosis: a mechanism of regulated necrotic
death
As early as 2005, a novel form of cell death, that showed
characteristics of necrosis, but unlike previous observa-
tions appeared to be tightly regulated, was identified. This
form of cell death was termed necroptosis (Degterev et al.,
2005). Necroptosis (Figure 4) is a category of necrosis that
is highly regulated (Li et al., 2012a, b). The process of
necroptosis is controlled in an apoptosis‐deficient environ-
ment by receptor‐interacting proteins 1 (RIP1) and 3
(RIP3). The most understood pathway of activation of
necroptosis is mediated by death receptors (Oliveira et al.,
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Figure 4 A summary of the steps involved in necroptosis
Necroptosis via TNF signalling and the deubiquitination of RIP1,
phosphorylation of RIP1 and RIP3, caspase 8 inactivation, and the
phosphorylation of MLKL. FADD, FAS‐associated death domain; MLKL,
mixed lineage kinase; RIP, receptor‐interacting protein; TNF, tumour
necrosis factor; TNFR1, TNF receptor 1; TRADD, tumour necrosis factor
receptor‐associated death domain.
Figure 5 A summary of the progression of a normal cell to an
oncotic and necrotic cell. Following a sudden shock to the cell and
upregulation of pro‐inflammatory cytokines, the cell losses permeability,
swells (oncosis) and then ruptures (necrosis), spilling its contents into
the surrounding tissue.
2018), most often by tumour necrosis factor receptor 1
(TNFR1), although the tumour necrosis factor‐related
apoptosis‐inducing ligand (TRAIL) and Fas receptors can
also induce necroptosis (Holler et al., 2000; Degterev et al.,
2005). When a ligand binds to TNFR1, it recruits pro‐
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Mark S D’Arcy
survival complex I, which consists of TNFR‐associated
death domain (TRADD) and RIP1 and several ubiquin E3
ligases. In complex I, the RIP1 is polyubiquinated;
subsequent deubiquitination of RIP1 results in the forma-
tion of either complex IIa or IIb. Complex IIa activates
caspase 8 and results in apoptosis, whereas when caspase 8
is inhibited, complex IIb is formed and activates necrop-
tosis.
To initiate necroptosis via complex IIb, RIP1 recruits
RIP3 and induces auto and trans‐phosphorylation, with a
consequent olygomerization of the phosphorylated RIP3.
This causes the assembly of a necrosome (a multiprotein
complex resembling amyloid). Together with RIP1 and 3,
mixed lineage kinase domain‐like pseudokinase (MLKL) is
also involved in necroptosis. RIP3 recruits MLKL and
phosphorylates it at Threonine 357/Serine 358. Following
phosphorylation, MLKL oligomerizes and then migrates to
the cell membrane from the cytoplasm of the cell. This
results in membrane permeabilization, possibly by the
MLKL binding to phosphatidylinositol lipids and cardio-
lipin; this results in necrosis and cell death (Wang
et al., 2014).
Oncosis: a switching mechanism between
apoptosis, autophagy and necrosis
The term oncosis is derived from the Greek word ‘onkos’,
which means swelling and is best thought of as a prelethal
pathway that ultimately leads to cell death (Levin, 1998). Its
main features are the swelling of both the cell generally and
the organelles of the cell specifically, together with an
increase in membrane permeability. As oncosis progresses,
there is a depletion of intracellular energy stores and an
eventual failure in the ionic pumps of the plasma
membrane (Majno and Joris, 1995). The result of oncosis
is a leakage of cellular debris into surrounding tissues and
consequently damage to surrounding cells (inflammation).
Oncosis can be induced by sudden shock to the cell, or in
some cases by infection of the cell by pathogens such as
Rotavirus (Periz et al., 1998).
Oncosis is the primary form of cell death observed in
ischaemic injury models (Majno and Joris, 1995) and can
lead to oncotic necrosis (Malhi et al., 2006). While
apoptosis results in shrinkage of the cell, margination of
chromatin in the nucleus and the formation of apoptotic
bodies, oncotic necrosis, in contrast, involves cellular
swelling, karyolysis, vacuolation and lysis, followed by the
release of cellular contents (Jaeschke and Lemaster, 2003).
Oncosis and apoptosis are linked via the energy‐requiring
(ATP‐dependent) nature of apoptosis. It should be noted
that a cell undergoing apoptosis may exhaust its ATP
supply and be unable to complete apoptosis; the result of
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Mark S D’Arcy
which is secondary necrosis, also characterised by swelling
and lysis. Conversly, if oncosis is inhibited, the stress to the
cell may induce apotosis (Jaeschke and Lemaster, 2003).
This switching from apoptosis to secondary necrosis, via
oncosis shows that apoptosis and oncotic necrosis are
closely related phenomena. It has been hypothesised that
apoptosis and oncosis are not distinct mechanisms, but are
instead opposite extremes of necroptosis (refer to earlier
description of necroptosis for further information). This
hypothesis (Lemasters, 1999) is backed up by the observa-
tion that opening of the mitochondrial membrane transi-
tion pore (MTP) is observed in both oncosis and apoptosis.
Specifically, the hypothesis states that an injury affecting a
small number of mitochondria could be repaired via
autophagy of damaged organelles, whereas if a sufficiently
large number of mitochondria are damaged, the resulting
high levels of released cytochrome c would activate the
intrinsic pathway of apoptosis if there remains enough
available ATP. If, however, the insult to the cell is severe
enough, then the cellular ATP levels would drop to a level
insufficient to induce apoptosis and the result would be
oncotic necrosis (Lemasters, 1999; Jaeschke and Lemaster,
2003). Therefore oncosis could act as a link between
autophagy, apoptosis and necrosis.
Figure 5 provides a generalised overview of oncosis and
its progression to necrosis.
Discussion
The various forms of programmed cell death have evolved
to clear away damaged and/or infected cells from affected
tissues in order that the surrounding healthy cells are better
able to perform their appropriate functions. Cell death may
result from a number of distinct and highly regulated
energy‐dependent processes (apoptosis, pyroptosis and
autophagy) or from energy independent processes (on-
cosis/necrosis). These distinct processes can be distin-
guished from one another based on their morphologic and
biochemical behaviour. More broadly, cell death can be
separated into primarily non‐inflammatory and pro‐
inflammatory categories. Apoptosis is generally non‐
inflammatory and results in the orderly removal of
damaged cells from tissues without inducing collateral
damage to surrounding cells. Oncosis, pyroptosis and
necrosis, however, result in an inflammatory reaction and
cause damage to surrounding tissues (Edinger and
Thompson, 2004; Bergsbaken et al., 2009). It may initially
seem plausible that apoptosis is always the preferred form
of cell death and that any pro‐inflammatory form of cell
death is to be avoided and is perhaps merely a result of a
failure in the appropriate activation of apoptosis, however,
evolution rarely produces a process as intricate as
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pyroptosis or necroptosis unless there is a selective
advantage to be gained to the organism. The authors
theorise that inflammatory forms of cell death have evolved
‘specifically’ in order to target and remove not just
individual cells, but multiple cells simultaneously. For
example, pyroptosis, which is triggered by a variety of
threats, such as invading bacteria helps to prevent the
spread of infection by killing groups of cells in an infected
replication niche of the tissue, whilst concurrently
attracting and activating neutrophils that respond to
released cytokines in the area of infection (Miao et al.,
2010; Kayagaki et al., 2011). Specifically, cells dying from
pyroptosis release damage‐associated molecular pattern
molecules (DAMPs), including IL‐1b. The DAMPs then
recruit immune cells to the site of infection (Aachoui, et al.,
2013), thus helping to remove infection from both the local
area and by generalised activation of the immune
system from the organism as a whole. Pyroptosis, therefore,
may induce a systemic immune response, whilst apoptosis
usually has only a local effect. Other forms of inflammatory
cell death such as necroptosis/necrosis can remove
damaged and/or cancerous cells from a ‘specific’ area of
tissue, and by attracting immune cells, result in generalised
death of populations of cells within that region. This helps
to ensure that any aberrant local cells that have not been
induced to begin a programme of apoptosis or another
form of cell death will, however, still potentially be
destroyed. This could, for example, help to destroy
populations of cancerous cells and thus prevent metastasis
of neoplastic cells to other tissues.
Like many other complex cellular pathways, there is the
potential for pathology due to abnormal activation of the
various forms of cell death. If a programme of cell death is
initiated prematurely, then a number of degenerative
diseases can occur. For example, apoptosis can result in
diseases such as hyperplasia in the peripheral lymphoid
organs and the liver resulting from malfunction of the Fas
system (Fas was discussed previously as a part of the
intrinsic pathway of apoptosis); this accelerates autoim-
mune diseases and tumourgenesis (Nagata, 1996).
Abnormal levels of apoptosis has also been associated
with a number of other pathological conditions, including
Parkinson’s disease (Tatton et al., 2003) and ulcerative
colitis (Wang et al., 2016). Inflammatory cell death such as
necroptosis has been associated with non‐alcoholic fatty
liver disease‐related carcinogenesis (Afonso et al., 2018)
and as discussed previously, pyroptosis is associated with
Salmonella or Shigella infection (Li et al., 1995). A number
of mouse‐model experiments have identified keratinocyte
necroptosis as a trigger of skin inflammation, which
suggests that keratinocyte necroptosis may be implicated
in the pathogenesis of human inflammatory skin diseases
(Bonnet et al., 2011; Dannappel et al., 2014). Note that a
589
A review of the major forms of cell death
mechanism for initiating inflammation in the skin may
have evolved as a useful mechanism to prevent invasion of
pathogens into the organism (Weinlich et al., 2013).
Targeting specific cell death pathways to treat disease
Understanding the mechanisms of apoptosis has led to the
development of the drug ABT‐737 and its oral derivative,
navitoclax. These two drugs are BH3 mimetics (Oltersdorf
et al,. 2005) and act by stimulating apoptosis by binding to
and inhibiting BCL‐2, BCL‐XL and BCL‐W, all of which
are inhibitors of apoptosis. Many B‐cell malignancies
overexpress anti‐apoptotic BCL‐2 enzymes, which results
in their growth and proliferation. ABT‐737 and navitoclax,
by blocking these enzymes, have proven to be an effective
treatment for such malignancies (Roberts et al., 2012). No
chemotherapeutics currently exist to target necroptosis,
however, targetting this pathway has been suggested as an
alternative or conjunctive to current apoptosis‐inducing
chemotherapeutics (Moriwaki et al., 2015), and one 2007
paper observed that the naturally occurring naphthoqui-
none compound shikonin induced cell death in the human
breast cancer cell model MCF‐7 and the HEK293 renal
cancer model by inducing necroptosis (Han et al., 2007),
which may lead to future necroptosis inducing drug
regimes. A 2017 paper has shown that chemotherapy can
induce pyroptosis in GSDME‐expressing cancer cells via
switching activation of caspase 3‐mediated apoptosis to
pyroptosis, although GSDME is silenced in most cancer
cells, this may lead to the development of novel therapies to
induce pyroptosis as a treatment for some cancers (Wang
et al., 2017; Zhang and Zhang, 2018). Autophagy serves to
protect healthy cells in times of stress and has also been
shown to be protective of cancer cells when they are
subjected to the stress of chemotherapy. One extra benefit
of autophagy to both healthy and neoplastic cells is that it
offers cells an alternative energy source during times of
metabolic stress (Mathew et al., 2007) such as during
chemotherapy. In 2014, the autophagy inhibitor Spautin‐1
was shown to enhance imatinib‐induced apoptosis in
chronic myeloid leukaemia (Shao et al. (2014), proof that
modifying autophagy is a valid target for treating cancer.
Conclusions
An increased understanding of the various forms of cell
death in recent decades has led to the development of more
effective clinical therapies for such diseases as cancer,
usually by inducing apoptosis. Although at the time of
publication, there are only a limited number of drugs
available that target necroptosis, pyroptosis or autophagy,
such drugs are under development and are likely to lead to
future therapies for a variety of diseases—including cancer,
590
Mark S D’Arcy
as a deeper understanding of their underlying mechanisms
is uncovered.
Acknowledgement
We thank the support of Hertfordshire International
College for their support in this work.
Conflict of interest
The author declares no conflict of interest.
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Received 3 November 2018; Revised 11 March 2019; accepted 23 March
2019.
Final version published online 25 April 2019.
Cell Biol Int 43 (2019) 582–592 © 2019 International Federation for Cell Biology