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Molecular Pathways
A Matter of Life or Death (or Both): Understanding
Autophagy in Cancer
William N. Hait, Shengkan Jin, and Jin-Ming Yang
Background
Definition
Autophagy is a conserved response to nutrient deprivation
found in yeast, plants, worms, flies, mice, and man (1). In
yeast, nutrient deprivation activates a genetic program that
results in (a) self-digestion of cytoplasm and organelles and the
recycling of amino acids and fatty acids for energy utilization
and (b) budding of an immortal spore. The process of
autophagy involves formation of a double-membrane vesicle
(‘‘autophagosome’’) in the cytosol that engulfs organelles and
cytoplasm and then fuses with the lysosome to form the
‘‘autolysosme,’’ where the contents are degraded and recycled
for protein and ATP synthesis (reviewed in ref. 2). The
formation of the autophagosome is mediated by a series of
autophagy-specific genes (ATG), whose products have been
classified into four groups based on function: (a) a autophagy
regulatory complex that responds to upstream events, such as
availability of nutrients; (b) a lipid kinase group that controls
vesicle nucleation; (c) an ubiquitin-like protein conjugation
system required for assembly of the autophagosome; and (d) a
group that is required for disassembly of ATG complexes (1).
Function
This form of self-digestion in unicellular organisms leads to
self-preservation in times of nutrient deprivation. However, if
left unchecked, autophagy has the potential of producing
terminal self-consumption. Not surprisingly, autophagy finds
its counterpart in multicellular organisms as high up the animal
kingdom as Homo sapiens. At the cellular level, nutrient
deprivation prompts cells to exit the cell cycle, shrink,
autodigest long-lived proteins and damaged organelles, and
recycle fatty acids and amino acids for synthesis of macromolecules or oxidation in mitochondria to maintain cellular
ATP. Autophagy may thus result in cellular destruction and/or
cellular ‘‘hibernation’’ until the supply of nutrients is restored.
Whereas autophagic cell death rests largely on indirect
evidence, autophagic cell survival is supported by direct
evolutionary, genetic, and biochemical studies (reviewed in
ref. 3).
Authors’ Affiliation: Departments of Medicine and Pharmacology, University of
Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School,The
Cancer Institute of NewJersey, New Brunswick, NewJersey
Received 1/3/06; revised 1/17/06; accepted 1/19/06.
Grant support: USPHS grants CA 43888 and CA 72720.
Requests for reprints: William N. Hait, Departments of Medicine and
Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood
Johnson Medical School, The Cancer Institute of New Jersey, 195 Little Albany
Street, New Brunswick, NJ 08903. Phone: 732-235-8064; Fax: 732-235-8094;
E-mail: haitwn@ umdnj.edu.
F 2006 American Association for Cancer Research.
doi:10.1158/1078-0432.CCR-06-0011
www.aacrjournals.org
Recent articles highlight aspects of autophagy that are
relevant to survival. For example, Kuma et al. (4) asked,
‘‘How do newborns survive after being cut off from the
maternal blood supply and before adequate nutrients are
available through suckling?’’ In this remarkable set of experiments, it was shown that at birth there is up-regulation of
autophagy in several organs, most notably heart and diaphragm, two muscles with abrupt increases in energy requirements at birth. Mice lacking Atg5, a gene whose product is
critical for the formation of autophagosomes, appeared normal
at birth but died within 24 hours of delivery. The Atg5 /
animals have reduced circulating amino acids and decreased
cardiac ATP and die presumably due to energy depletion.
Electrocardiograms done on the newborns pups revealed
cardiac damage. Thompson’s laboratory (5) examined the role
of autophagy in the long-term survival of immortalized
hematopoietic precursors and primary bone marrow cultures
deprived of an obligate growth factor (interleukin-3). In the
absence of growth factors, there was decreased expression of
membrane nutrient transporters leading to nutrient deficiency.
They found that cells in which apoptosis was inactivated by
deleting bax and bak survived for >6 weeks in the absence of
interleukin-3 by using autophagy to supply precursors for
ATP. On readdition of interleukin-3, cells increased nutrient
transport and recovered size and the ability to proliferate.
Finally, Boya et al. (6) found that nutrient-deprived HeLa cells
underwent autophagy rather than apoptosis (believed to occur
through sequestration of damaged mitochondria). Consistent
with its prosurvival role, blocking the autophagic pathway with
either small interfering RNAs against key autophagy genes
(beclin1, Atg10, or Atg12) or with drugs (3-methyladenine,
hydroxychloroquine, bafilomycin A1, or monensin) triggered
apoptosis.
Recent Advances
Regulation
Levine’s group provided additional insights into the role of
autophagy in what may be a delicate balance between cell
death and survival. Beclin-1 (BECN1) is the mammalian
homologue of the yeast Atg6 autophagy gene, which is
involved in early autophagosome formation (7, 8). Monoallelic deletion of BECN1 in mice enhanced tumorigenesis
(9, 10), initially suggesting that autophagy was a cell death
pathway. However, it was later shown that embryonic stem
cells that are null for BECN1 have no changes in sensitivity
to death stimuli and that tumors from BECN1 haploinsufficient mice did not show depletion of beclin-1 protein (3).
Levine’s group showed that bcl-2 binds to beclin-1 protein
and dampens autophagic cell death (11). Using beclin-1
mutants that fail to bind bcl-2, they observed excessive
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Molecular Pathways
autophagy and cell death. These data suggest that bcl-2 can
regulate both autophagy and apoptosis and that bcl-2 may
calibrate autophagy to levels that are compatible with
survival. Beclin-1 can also bind to class III phosphatidylinositol 3-kinase (PI3K) and form a complex that is required for
the activation of autophagy (12).
Autophagy is controlled by pathways that impinge on the
mammalian target of rapamycin (mTOR). The mTOR pathway
integrates the cellular response to growth factors and nutrients
through regulation of protein synthesis (Fig. 1). In yeast, TOR
provides a link between cell growth and the availability of
extracellular nutrients. In mammals, mTOR is also regulated by
growth factors through the class I PI3K/Akt pathway (13) and
by the down-regulation of surface nutrient transporters during
growth factor withdrawal (5). Activation of TOR in yeast
inhibits autophagy via phosphorylation of the APG1-APG13
complex (14), a process inhibited by rapamycin in both yeast
and mammalian cells (14). Substantial cross-talk exists between
the PI3K/Akt pathway and the Ras/Raf/extracellular signalregulated kinase 1/2 pathways (Fig. 1). For example, epidermal
growth factor activation of both extracellular signal-regulated
kinase 1/2 and Akt blocked the induction of autophagy,
whereas PTEN, a negative regulator of Akt, stimulated
autophagy in HT-29 colon cancer (15).
Protein synthesis
Tight regulation of protein synthesis is essential for cell
survival during nutrient and growth factor deprivation because
Fig. 1. A, in the presence of nutrients (glucose, amino acids, and growth factors), protein synthesis is stimulated and autophagy is inhibited. This is mediated through
activation of mTOR (via activation of PI3K and Akt and inactivation of the tuberous sclerosis complexTSC1and TSC2). mTOR phosphorylates S6 kinase and increases the
translation of mRNAs that encode ribosomal and other proteins involved in translation. This initiates translation by phosphorylating 4EBP1, an inhibitor of initiation, causing its
disassociation from eIF4E. Active eIF4 promotes cell proliferation by increasing translation of cyclin D1, c-Myc, and vascular endothelial growth factor. mTOR and S6 kinase also
release the cellular check on peptide elongation by phosphorylating and inactivating eEF-2 kinase. eEF-2 kinase phosphorylates eEF-2, a 100-kDa protein that mediates the
translocation step in peptide-chain elongation by inducing the transfer of peptidyl-tRNA from the ribosomal A to P site. Phosphorylation of eEF-2 atThr56 by eEF-2 kinase
decreases the affinity of the elongation factor for ribosomes and terminates elongation. Activation of TOR in yeast inhibits induction of autophagy via phosphorylation of the
APG1-APG-13 complex, a process inhibited by rapamycin in both yeast and mammalian cells. B, formation of the autophagosome.This process requires the coordinated efforts
of a series of gene products that respond to nutrient deprivation (autophagy regulatory complex), lipid kinase signaling molecules that participate in the formation of vesicles,
ubiquitin-like proteins that complete vesicle formation, and a complex of proteins that mediate the disassembly of the autophagosome. The initial step is the envelopment of
cytoplasmic materials into a phagophore or isolating membrane. This leads to the sequestration of cytoplasm into the autophagosome, which are characterized by a double
membrane decorated with microtubule-associated protein 1light chain 3 (LC3). The fusion of autophagosomes with lysosomes to for the autolysosome leads to the
acidification and degradation of cytoplasmic components for recycling of amino acids and fatty acids for energy production.
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Autophagy and Cancer
protein synthesis accounts for the consumption of up to 50% of
cellular energy (16). The majority of energy is used during
peptide elongation either through the hydrolysis of 2 mol GTP
for each added amino acid or during the charging of aminoacyltRNAs where 1 mol ATP is hydrolyzed per each charged amino
acid. Therefore, for cells to survive under conditions of nutrient
deprivation, protein synthesis must be limited to conserve
energy; if not, depletion of ATP will impede the function of
membrane transporters, thereby destroying electrochemical
gradients and thus leading to necrotic cell death (3).
In the presence of adequate nutrients, protein synthesis is
stimulated and autophagy is inhibited as depicted in Fig. 1. This
is mediated through activation of mTOR via PI3K and Akt and
inactivation of the tuberous sclerosis complex TSC1 and TSC2.
mTOR phosphorylates S6 kinase and increases the translation
of mRNAs that encode ribosomal and other proteins involved
in translation (17). Protein translation is then initiated by
phosphorylating 4EBP1, an inhibitor of initiation, causing its
disassociation from eukaryotic initiation factor 4E (eIF4E).
Active eIF4 promotes cell proliferation by increasing translation
of cyclin D1, c-Myc, and vascular endothelial growth factor
(18). In the presence of adequate nutrients/growth factors,
three enzymes, AMP kinase, mTOR, and S6 kinase, promote
peptide elongation by regulating eukaryotic elongation factor-2
(eEF-2) kinase (Fig. 1).
In the absence of nutrients, protein synthesis is inhibited and
autophagy is activated. Nutrient/growth factor deprivation and
subsequent ATP depletion induce autophagy by inhibiting
mTOR (via activation of TSC2 by AMP kinase) and by decreasing
phosphorylation of S6 kinase and 4EBP1 (19, 20). Under these
conditions, initiation of translation is repressed by the reformation of the 4EBP4/eIF4E inhibitory complex, and protein
elongation is inhibited through activation of eEF-2 kinase by
the increased activity of AMP kinase and decreased activity of
mTOR and S6 kinase. Thus, eukaryotic cells have evolved a
mechanism to withstand nutrient deprivation by decreasing
energy utilization through inhibiting protein synthesis and
producing ATP through recycling of amino acids produced from
autophagic digestion of cellular organelles and proteins.
eEF-2 kinase is a structurally unique enzyme (21) whose
activity is increased in cancer (22). An early clue to the
importance of eEF-2 kinase in cell survival came from an
unlikely source (hibernation experiments in squirrels). When
captured and placed in a hibernaculum (low temperature, dim
light, and no nourishment), these creatures survive by reducing
body temperature, respiratory rate, heart rate, blood pressure,
cardiac output, cerebral blood flow, and metabolism. Hibernating squirrels increase the phosphorylation of eEF-2 in brain
and liver through activation of eEF-2 kinase and inhibition of
PP2A, the cellular phosphatase that dephosphorylates eEF-2
(23). Accordingly, during hibernation, decreasing protein
synthesis through inhibition of elongation conserves energy.
eEF-2 kinase is tightly regulated by the availability of growth
factors and nutrients via insulin-dependent and non-insulindependent regulation of mTOR through the class I PI3K/Akt
pathway. Proud’s group showed that when nutrients are
available the activity of eEF-2 kinase is inhibited by phosphorylation at Ser78 and Ser366 by mTOR and S6 kinase, respectively
(16, 24). In times of ‘‘famine,’’ the activity of eEF-2 kinase is
increased by phosphorylation at Ser398 by AMP kinase, which
is activated at high AMP/ATP ratios (25). Phosphorylation of
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eEF-2 at Thr56 by eEF-2 kinase decreases the affinity of the
elongation factor for ribosomes and terminates elongation.
During times of nutrient/growth factor deprivation when
mTOR and S6 kinase activities are decreased and AMP kinase
is increased, eEF-2 kinase is activated and transiently inhibits
protein elongation, thereby conserving energy (Fig. 1).
Oncogenesis
As mentioned above, BECN1 is the mammalian homologue
of the yeast Atg6 autophagy gene and was initially identified
through its interactions with bcl-2 (7, 8). BECN1 promotes
autophagy in breast cancer cells and maps to a cancer
susceptibility locus (17q21) that is monoallelically deleted in
40% to 75% of breast and ovarian cancer (26 – 28). Monoallelic
deletion of beclin1 in mice enhanced tumorigenesis leading to
the development of carcinomas of the lung and liver as well as
lymphomas (9, 10). Overexpression of beclin-1 in MCF-7 cells
increased autophagy on amino acid starvation (8) and inhibited
proliferation without increasing cell death. Inhibition of PI3K by
3-methyladenine decreased beclin-1-induced autophagy in
MCF-7 cells (8), which may be regulated by DAP kinase and
DRP-1 (29). BECN1 transfectants were reportedly ‘‘less tumorigenic’’; however, the authors did not rule out the possibility that
this was due to lowered proliferation. Although the BECN1 gene
is haploinsufficient in MCF-7 breast cancer, treatment with
tamoxifen induced autophagy (30).
Accumulating evidence points to the importance of autophagy in cancers (reviewed in ref. 31). One of the most carefully
studied has been glioblastoma multiforme due in good
measure to the work of Kondo’s laboratory (31). For example,
radiation (32), platelet-derived growth factor receptor antagonists (33), rapamycin (34), and temozolomide (35) all induce
autophagy in a variety of glioma cell lines. Our recent studies
indicate that eEF-2 kinase may play an important role in
autophagic survival of glioma cells and that targeting this
enzyme may accelerate cell death (36). As shown by us (36)
and others, the activity of mTOR and S6 kinase are decreased by
nutrient/growth factor deprivation and this relieves the
inhibition of eEF-2 kinase activity produced by these two
enzymes (16, 24). Because protein synthesis consumes more
ATP than any other cellular process, the activation of eEF-2
kinase conserves energy through terminating protein elongation and thereby supports survival during times of nutrient
stress. To test this model in glioma cells, we blocked starvationinduced activation of eEF-2 kinase with small interfering
RNA and measured its effects. Stable glioma cell populations
depleted of eEF-2 kinase by short hairpin RNA [T98GeEF-2K( )]
showed decreased phosphorylation of eEF-2 at Thr56 and
autophosphorylation of eEF-2 kinase compared with isogenic
cell cultures transfected with a nontargeting short hairpin RNA
vector (36). T98GeEF-2K( ) glioma cells had decreased ability to
undergo autophagy as measured by decreased conversion of
LC3-I to LC3-II, lack of autophagosomes by electron microscopy, and decreased acid vesicle organelle formation (36). LC3
is the mammalian homologue of an essential yeast autophagy
protein, Atg8. During autophagy, LC3-I is cleaved and
conjugated to phosphatidylethanolamine to form LC3-II. It
is the processing of LC3-I to LC3-II that is essential for the
formation of the autophagosome, and LC3-II levels are
proportional to the number of autophagic vacuoles (37).
Furthermore, cells depleted of eEF-2 kinase were more sensitive
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Molecular Pathways
to nutrient withdrawal as manifested by accelerated loss of
viability when grown in serum-free medium. In contrast,
overexpression of eEF-2 kinase in T98G glioma cells increased
autophagy (36). This intolerance to deprivation is consistent
with the depletion of ATP due to ongoing protein synthesis in
the face of inadequate nutrients.
Therapeutic Implications
Targeting autophagy for cancer treatment: pros
and cons
If autophagy serves as a dominant survival pathway for
cancer cells living on the edge of an adequate blood supply,
nutrients, and growth factors, then blocking this survival
pathway should provide a means to kill the cancer cells that
are often resistant to many forms of treatment, including
radiation, chemotherapy, and growth factor antagonists.
Similarly, if autophagy protects against apoptotic cell death
by sequestering damaged mitochondria, then blocking autophagy should accelerate killing by shuttling cells into more
reliable death pathways. Alternatively, if autophagy is a
dominant death pathway, then inhibition could promote
survival. Chemotherapeutic drugs (34, 35), growth factor
antagonists (33), and radiation (32) can activate autophagy
pathways in models of glioblastoma and other tumors, but
whether autophagy is a protective cellular response to cell
damage or growth factor withdrawal or inhibition or a deathpromoting activity remains to be fully elucidated. Inhibitors of
autophagy have been reported to both increase and decrease
cell death following treatment with anticancer drugs (38 – 42).
To illustrate this point, consider the withdrawal of a growth
factor (e.g., estradiol) in the treatment of breast cancer. If the
increase in autophagy observed by several labs was a
mechanism of cell death elicited by antiestrogen treatment,
then inhibition of autophagy should decrease cell kill.
Conversely, if the onset of autophagy represented a survival
mechanism, then inhibition of autophagy should ultimately
increase cell death perhaps by shuttling cells into more
permanent death pathways. At this point, few studies have
rigorously explored these possibilities in patients, which will be
crucial in determining how to deal with this highly conserved
cellular response.
There are several potential ways to envision targeting the
autophagy pathway. For example, one could disrupt autophagy
by the following approaches: (a) block the signaling pathways
that initiate autophagy; target key components involved in the
formation of the autophagosome (autophagy gene products);
(b) inhibit the fusion of the autophagosome with lysosomes to
block autolysosome formation (bafilomycin A and antimitotic
drugs); (c) disrupt the recycling of autodigested substrates used
for resynthesis of ATP; or (d) block the cell’s ability to conserve
energy by preventing the termination of protein synthesis. A
target that is activated rather than inhibited (e.g., mTOR, Akt,
and PI3K) to initiate our sustain autophagy would be
preferable, because it is far easier to block a target than to
activate one. In that regard, eEF-2 kinase becomes increasingly
attractive because it is overexpressed in many forms of cancer
(22, 43) and it is activated during autophagy (36); its activity
terminates protein elongation and conserves energy (44); and
its unique structure makes this kinase amenable to selective
inhibition (21, 43). Conditional inactivation of eEF-2 kinase by
genetic (conditional knockout) or pharmacologic approaches
in cancer models would therefore help address the proper role
of autophagy in cancer treatment.
Summary
Autophagy is a highly conserved pathway that can be used for
survival during nutrient and growth factor deprivation. Under
certain circumstances, it seems that autophagy may serve as a
pathway to cell death. Already, it is becoming increasingly clear
that autophagy is involved in cancer formation, survival, and
response to several forms of cancer treatments. A detailed
understanding of how this pathway is regulated is now
emerging and will allow translation of this information into
new approaches to cancer treatment.
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A Matter of Life or Death (or Both): Understanding
Autophagy in Cancer
William N. Hait, Shengkan Jin and Jin-Ming Yang
Clin Cancer Res 2006;12:1961-1965.
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