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REVIEW ARTICLE
From the Division of Pediatric Oncology, German Cancer
Research Center, Heidelberg, Germany; and University Children's
Hospital, Ulm, Germany.
Anticancer treatment using cytotoxic drugs is considered to
mediate cell death by activating key elements of the apoptosis program
and the cellular stress response. While proteolytic enzymes (caspases)
serve as main effectors of apoptosis, the mechanisms involved in
activation of the caspase system are less clear. Two distinct pathways
upstream of the caspase cascade have been identified. Death receptors,
eg, CD95 (APO-1/Fas), trigger caspase-8, and mitochondria release
apoptogenic factors (cytochrome c, Apaf-1, AIF), leading to the
activation of caspase-9. The stressed endoplasmic reticulum
(ER) contributes to apoptosis by the unfolded protein response pathway,
which induces ER chaperones, and by the ER overload response pathway,
which produces cytokines via nuclear factor- In an overall scenario, the development of
malignant tumors results from deregulated proliferation or an inability
of cells to undergo apoptotic cell death.1,2
Anticancer drugs inhibit proliferation and induce apoptosis in
sensitive tumor cells.3,4 The cellular targets for
different cytotoxic agents are diverse. Thus, anticancer drugs are
classified as DNA-damaging agents (cyclophosphamide, cisplatin,
doxorubicin), antimetabolites (methotrexate, 5-fluorouracil), mitotic
inhibitors (vincristine), nucleotide analogs (6-mercaptopurine), or
inhibitors of topoisomerases (etoposide). The common underlying mechanism for chemotherapy-induced apoptosis might be damage to DNA,
lipid components of cell membranes, and cellular proteins causing an
imbalance of the cellular homeostasis commonly designated as cellular
stress. This in turn initiates a complex cascade of stress-inducible
signaling molecules in an attempt to return the cell to its previous
equilibrium. As for the response to DNA damage, this may include
cell-cycle regulation and repair mechanisms. The type and dose of
stress within the cellular context appears to dictate the outcome of
the cellular response, which is intimately converted to complex
pathways mediating cell-cycle control or cell death. Apoptosis seems to
be induced if damage exceeds the capacity of repair mechanisms. Here,
we review mechanisms of cellular stress signaling with respect to their
integration into apoptosis pathways.
Caspases as death effectors
Mitochondria and activation of caspases
Bcl-2 family proteins play a central role in controlling the
mitochondrial pathway. In humans, more than 20 members of this family
have been identified to date, including proteins that suppress (Bcl-2,
Bcl-XL, Mcl-1, Bfl-1/A1, Bcl-W, Bcl-G) and proteins that promote (Bax, Bak, Bok, Bad, Bid, Bik, Bim, Bcl-Xs, Krk, Mtd, Nip3,
Nix, Noxa, Bcl-B)12-15 apoptosis. Bcl-2 proteins localize or translocate to the mitochondrial membrane and modulate apoptosis by
permeabilization of the inner and/or outer membrane, leading to release
of cytochrome c or by stabilizing barrier function. Most Bcl-2 family
proteins are capable of physically interacting, forming homodimers or
heterodimers, and functioning as agonists or antagonists of each
other.12 Additionally, Bcl-XL binds and inactivates Apaf-1, whereas proapoptotic members can displace Bcl-XL from Apaf-1, allowing Apaf-1 to activate caspase-9.
Thus, Bcl-2 family members can directly influence the response to
cellular stress.8,11 Control of chemotherapy-induced
apoptosis by Bcl-2 or Bcl-XL has been suggested by a number
of experimental and clinical studies. Increased Bax levels in several
tumor cells have been associated with favorable responses to
chemotherapy in vivo. Human colorectal cancer cells lacking functional
Bax genes were found to be partially resistant to the apoptotic effects
of chemotherapeutic agents. Vice versa, resistance to chemotherapy was
found to be related to increased levels of expression of Bcl-2 and
Bcl-XL16,17 in some studies.18
Death receptors and activation of caspases
The mitochondrial and caspase apoptotic pathways are intimately
connected. For example, caspase-8 cleaves the cytosolic proapoptotic protein Bid. Bid is a member of the BH3 domain-only subgroup of Bcl-2
family members. This set of proapoptotic proteins shares its only
sequence homology within the BH3 amphipathic Antiapoptotic DED-containing proteins such as BAR,20 Bap31,21 and FLIP22 may compete with adaptor proteins such as FADD for binding to procaspases-8 and -10, thus reducing the amount of caspase processing and activation. Apoptosis induction through death receptors may be antagonized by a number of decoy receptors (DcR1 [TRAIL-R3], DcR2 [TRAIL-R4], DcR3 [CD95]) that lack the death domain and compete for the cognitive death ligands without inducing apoptosis.23,24 Inhibitors of caspase-action: IAP proteins A family of endogenous direct inhibitors of caspases (IAPs) are conserved throughout animal evolution with homologies in viruses, yeast, flies (Drosophila), worms (C elegans), mice, and humans.25-28 All IAPs contain 1 to 3 baculovirus IAP repeat (BIR) domains, which may be involved in the inhibition of caspase activity. In addition, most also possess a carboxy-terminal RING finger motif. The mammalian IAPs, X-IAP, cIAP-1 (MHIB), cIAP-2 (MIHC), ML-IAP, and livin, inhibit active caspase-3 and -7 and the activation of caspase-9 mediated by Apaf-1-cytochrome c, while survivin has been implicated in regulation of cell cycle and mitosis. Because survivin, ML-IAP, and livin are overexpressed in many cancers but not in normal adult tissues, these molecules represent possible targets for the development of drugs that selectively eliminate cancer cells.29-31A mammalian IAP inhibitor known as Smac or DIABLO binds to IAP family members and neutralizes their antiapoptotic activity. This regulatory effect seems to be part of a mitochondrial positive feedback loop because Smac/DIABLO is a mitochondrial protein that is released together with cytochrome c into the cytosol in apoptotic cells.5 Ligation of death receptors and cellular stress-induced apoptosis Recent data from our own laboratory and others suggested that anticancer drug-induced cell death may involve the CD95 system. CD95 and CD95-L are constitutively expressed in many tissues and further induced by the appropriate stimuli. Mutations or failure to up-regulate CD95 and CD95-L may result in apoptosis defects of tumor cells.32 Mutation of CD95 in humans or lpr mice results in a lymphoproliferative syndrome caused by the inability to delete long-term activated T cells.33-37 Splenocytes from lpr mice have been found to exhibit decreased sensitivity toward -irradiation- or heat shock-induced apoptosis38
corresponding to a suggested function of the CD95 system in cellular
stress-induced apoptosis. Several investigations have shown that cell
lines derived from leukemia, hepatoma, neuroblastoma, colon, breast
cancer, brain tumors, and small lung cell carcinoma increase expression
of CD95-L upon treatment with chemotherapeutic drugs or
radiation.39-52 Drugs that have been observed to enhance
CD95-L messenger RNA levels include doxorubicin, etoposide, teniposide,
methotrexate, cytarabine, cisplatin, bleomycin, and 5-fluorouracil.
Elevated levels of CD95-L protein have also been detected after many of
these treatments, although the increase sometimes appears smaller in
magnitude than the increase in messenger RNA.53
Furthermore, expression of the CD95 receptor increased after drug
treatment, especially in cells bearing wild-type
p53.44-46,50,54,55 A direct correlation was observed
between CD95 receptor density and drug sensitivity, and mutant cell
lines resistant to agonistic antibodies to CD95 were also resistant to
anticancer drugs.43,56-58 The most significant result from
these studies was that drug-induced apoptosis was prevented in some
instances by soluble blocking CD95 receptors, neutralizing CD95-L
antibodies, or dominant negative FADD, which prevents signaling of
death receptors.39-43,45-48,50-52 Thus, cellular stress
may involve interaction of CD95 with its ligand and may lower the
threshold for the induction of apoptotic signals. Although CD95/CD95-L
interaction may regulate certain types of stress-induced apoptosis,
CD95-L-independent oligomerization of the CD95 receptor by cytotoxic
drugs and UV irradiation can be sufficient to activate caspase-8 in a
FADD-dependent manner.59-61 Other death systems, such as
the TNF or TRAIL system, may be involved in stress-induced apoptosis,
thereby contributing to the redundancy of the apoptosis network under
conditions in which one system is blocked.47
However, other results are incompatible with the view that death
receptor signaling is essential for drug-induced apoptosis. Comparison
of CD95-sensitive and CD95-resistant Jurkat T-lymphoma cells revealed
no difference in their sensitivity to a broad range of chemotherapeutic
drugs. Blockade of CD95 signaling by antibodies that neutralize either
the receptor or CD95-L did not protect lymphoma cells against
drug-induced cell death.62,63 Also, CD95-deficient
thymocytes from lpr mice or cells that express FLIP or a
dominant-negative construct of FADD did not exhibit increased
proliferation to The relative contribution of death receptor versus mitochondrial pathways in stress-induced apoptosis may vary depending on the dose and kinetics but may also reflect the existence of 2 different cell types with respect to CD95 signaling: Type I cells undergo CD95-mediated apoptosis without the involvement of mitochondria, whereas type II cells require the release of cytochrome c from mitochondria in order for CD95 to exert its apoptotic effect. At the molecular level, these 2 cell types differ principally in the amount of caspase-8 recruited to CD95 via the adapter molecule FADD to form the DISC. Whereas type I cells contain large amounts of DISC in response to anti-CD95 antibodies, type II cells do not and thus are dependent on stimulation of the intrinsic apoptotic pathway to undergo cell death. Mitochondria are activated in both type I and type II cells but are dispensable for the death of type I cells.5,9,79 With respect to drug-induced apoptosis, a type I response (depending on cross-linked CD95 receptors) has been found in some cell types.80 Caspase-independent apoptosis Cell death is generally classified into 2 large categories: apoptosis, representing "active" programmed cell death, and necrosis, representing "passive" cell death without (known) underlying regulatory mechanisms. However, there are forms of cell death that cannot be readily classified as apoptosis or necrosis for
example, when cells die by cytoplasmic and membrane changes seen in
apoptosis but do not exhibit DNA and/or nuclear
fragmentation.81-83 Also, z-VAD-fmk could not rescue
cells from apoptosis induced by the overexpression of Bax, although
caspase-3 activation and nuclear fragmentation were clearly
blocked.84,85 In addition, a mixture of apoptotic and
necrotic morphology has been found in some cells, eg, in TNF- and
CD95-induced cytotoxicity.86,87 This necroticlike cell
death depends on an intact downstream intracellular signaling pathway
most likely involving generation of reactive oxygen species (ROS),88 whereas activation of caspases seems to be
dispensable.87
The cellular components of caspase-independent apoptosis are not identified so far. In most apoptotic systems z-VAD-fmk does not block mitochondrial changes, such as loss of the membrane potential, production of ROS, or the release of apoptogenic factors such as cytochrome c and AIF.8 Thus, despite caspase inhibition, apoptotic morphology may still be induced by 2 factors: AIF and Bax or Bax-like proteins. How AIF and other released proteins trigger apoptosis in the absence of caspases is unknown. These molecules may activate proteases such as the calcium-dependent calpain proteinases or the lysosomal cathepsins, which can partially substitute caspases but in a less efficient way.81 Cathepsins released from lysosomes cleave Bid, which activates the mitochondrial apoptosis pathway,89 whereas calpains cleave Bax, which promotes cytochrome c release.90-92 Furthermore, calpains are known to cleave and thereby inactivate the cytoprotective endoplasmic reticulum (ER) chaperone glycoprotein GRP94, which contributes to apoptosis.93
JNK signaling and cellular stress-induced apoptosis Jun N-terminal kinase (JNK) signaling and c-Jun/AP-1 have been implicated in various, often opposing cellular responses, including proliferation, differentiation, and cellular stress-induced apoptosis (Figure 2). The AP-1 family of transcription factors consists of members of the Jun, Fos, and ATF-2 subfamilies.94 Mammalian Jun proteins include c-Jun, Jun B, and Jun D. Fos proteins include c-Fos, FosB, Fra-1, and Fra-2. ATF proteins that participate in forming AP-1 dimers are ATF-2 and ATF-a. Depending on the stimulus and cellular context, the composition of the dimeric AP-1 complex varies between different members of the Jun, Fos, and ATF family. The activity of individual AP-1 subunits can be regulated either by transcription increasing the intracellular concentration of the proteins or by posttranslational modifications and interaction with other proteins such as members of the mitogen-activated protein kinase (MAPK) signaling pathways.
The MAPK pathway includes the subfamilies extracellular signal-regulated kinase (ERK), JNK, and p38. These different MAPKs are members of separate modules and are regulated by distinct extracellular stimuli. For example, ERKs are activated by receptor tyrosine kinases and provide proliferation or differentiation signals. JNK and p38-type MAPKs are activated predominantly by stress stimuli and pathogenic insults but in some cell types also by mitogens. All 3 classes of MAPKs are involved in the regulation of distinct AP-1 components. c-Jun is regulated by JNK phosphorylation and in some cell types also by ERK-mediated mechanisms. c-Fos is a substrate for regulatory phosphorylations by ERK, and ATF-2 is regulated by JNK and p38 kinases.95 Due to this complex regulation of AP-1 factors, the range of biological responses is broad. In the following, we focus on how activation of JNK and c-Jun/AP-1 contributes to cellular stress-induced apoptosis. JNK protein kinases are encoded by 3 genes. While Jnk1 and Jnk2 genes are ubiquitously expressed, expression of the Jnk3 gene is restricted to the brain, heart, and testis. Alternative splicing generates at least 10 different JNK isoforms, which might differ in their substrate specificity. JNK signaling can be turned off by dual-specificity MAPK phosphatases, which often function in a negative feedback loop.96-99 JNK signaling may contribute to apoptosis100-112 or may be
dispensable for apoptosis113 and even inhibit apoptosis to
promote proliferation and differentiation.114,115 Thus,
the effects of JNK on cellular responses appear to depend on the cell
type and the context of other signals received by the cell. A clear
proapoptotic role of JNK has been demonstrated in studies of mice with
targeted disruption of the neuronal gene Jnk3.110
JNK3 Among the proapoptotic targets of c-Jun are the promoters of CD95-L and
TNF- Substrates for JNK activity also include p53. Dependent on the cellular context, JNK either destabilizes p53 by binding, promoting ubiquitin-mediated degradation, or stabilizes p53 by phosphorylation, whereby inhibiting ubiquitin-mediated degradation.129,130 Furthermore, JNK may be involved in regulating transcription of the p53 gene because c-Jun can repress the p53 promoter.131 These data suggest that JNK may be important for controlling the level of p53 expression by regulating the half-life of p53, although these data are discussed with controversy. An additional potential target of proapoptotic signaling by JNK is the transcription factor c-Myc. Recent studies indicate that c-Myc interacts with JNK and is phosphorylated at Ser62 and Thr71.132 Apoptosis induced by ectopic c-Myc expression in serum-starved cells is associated with increased JNK activity, as concluded from dominant-negative experiments leading to inhibition of JNK signaling and c-Myc-stimulated apoptosis. However, because JNK-induced apoptosis does not require either ectopic c-Myc expression or serum starvation, the role of c-Myc phosphorylation by JNK is unclear. Despite a function of c-Jun in the regulation of CD95-L, TNF- In conclusion, JNK may induce apoptosis by transcription-dependent signaling (leading to secretion of death ligands), by transcription-independent signaling (leading to cytochrome c release from mitochondria), or by phosphorylation-dependent posttranslational proapoptotic signaling yet to be identified. It is possible that these mechanisms may function separately, but these mechanisms may also cooperate to induce death. Taken together, JNK signaling in combination with other factors, such as the suppression of proliferation pathways, may induce apoptosis following cellular stress. Endoplasmic reticulum and cellular stress-induced apoptosis As a protein-folding compartment, the ER is exquisitely sensitive to alterations in homeostasis, for example, induced by cellular stress. Different stimuli signal through several protein kinases to up-regulate the protein-folding capacity of the ER by activation of 2 signaling pathways: the unfolded protein response pathway, leading to the induction of ER chaperones such as grp78/Bip via the C/EBP homologous transcription factor CHOP/GADD153,136 and the ER overload response pathway, leading to the production of cytokines via nuclear factor B (NF-B) (Figure 3).
Both pathways help the cell to cope with incorrectly folded or
accumulated proteins in the ER but may also contribute to its
elimination when abnormalities become too extensive.137
Consistent with this idea, both CHOP/GADD153 138 and
NF-B have been implicated in apoptosis regulation.139 Another mediator of death signaling may be caspase-12, which is localized to the ER and is proteolytically activated by ER stress. Mice
that are deficient in caspase-12 are resistant to ER stress-induced apoptosis, but their cells undergo apoptosis in response to other death
stimuli.140
Although the effects of Bcl-2 on the mitochondria have been studied intensively, little is known about the effects of Bcl-2 on the ER, where antiapoptotic Bcl-2 family proteins are also localized. Several ER membrane proteins have been reported to interact with Bcl-2 family members to enhance their antiapoptotic effect. Among them is Bax inhibitor I141 and the Bcl-2/Bcl-XL-associated Bap31.21,142,143 Similarly, but in a proapoptotic manner, the Schizosaccharomyces pombe calnexin chaperone homolog Cnx1 interacts with Bak,144 whereas the calcium pump SERCA (sarcoplasmic/endoplasmic reticulum calcium-ATPase) interacts with Bcl-2,145 and members of the ER-anchored reticulon family such as NSP-C and RTN-XS bind to Bcl-XL and Bcl-2,146 thereby contributing to apoptosis. Apoptotic agents perturbing ER functions such as brefeldin A induce the release of cytochrome c from mitochondria that is blocked by Bcl-2 derived from either mitochondria or ER. Brefeldin A-induced cytochrome c release occurred in a caspase-8- and Bid-independent manner and was followed by caspase-3 activation and DNA/nuclear fragmentation.147 Overexpression of calreticulin, an ER luminal protein, sensitized cells to apoptosis induced by thapsigargin (an agent that promotes ER stress by depletion of luminal calcium stores) and staurosporine (a potent inhibitor of phospholipid/calcium-dependent protein kinase). This correlated with an increased release of cytochrome c from mitochondria. Calreticulin-deficient cells were significantly resistant to apoptosis, correlating to a decreased release of cytochrome c from mitochondria and low levels of caspase-3 activity.148 ER stress may also activate JNKs.149 Lysates from
ER-stressed rat pancreatic cells treated with thapsigargin, tunicamycin (which block protein glycoslyation), or dithiothreitol (which interferes with disulfide bond formation) all exhibited increased JNK
activity.150 Activation of JNKs by ER stress,
although always present, varies in magnitude depending on cell type and
is particularly pronounced in cells with a well-developed ER. Coupling
of ER stress to JNK activation may be mediated by a mammalian homolog
of yeast IRE1, which activates chaperone genes. Overexpression of IRE1 or its mammalian homolog leads to JNK activation, and
IRE1 Together, these findings implicate that the ER, via specific components of its luminal environment or by interaction among ER, mitochondria, and JNK, may play an important role in the modulation of cell sensitivity toward apoptosis. p53 and cellular stress-induced apoptosis Various stress stimuli such as cytotoxic drugs,-irradiation,
heat shock, hypoxia, osmotic shock, and DNA-damaging agents stabilize
the tumor suppressor protein p53, which promotes cell-cycle arrest to
enable DNA repair or apoptosis to eliminate defective cells152 (Figure 4). However,
it is still largely unknown how p53 selects the pathways of G1 arrest
or apoptosis. In this context, the proline-rich domain (residues
64-92)153,154 and a recently identified transcriptional
activation domain (residues 43-63)155 have been suggested
to be necessary for mediation of apoptosis because deletion of either
of these 2 domains abolishes this activity. On the other hand, it has
been shown that phosphorylation and acetylation play important roles
for regulating biological activities of p53.156,157
Although the roles of these modifications are not fully characterized,
they are likely to play roles in regulating the binding of p53 with its
negative regulator, Mdm2. Other negative regulatory mechanisms involve
binding of JNK to p53, which mediates ubiquitination and proteolytic
removal of p53,129 and the retinoblastoma gene product
(Rb), which prevents the apoptotic function of p53.158,159 Both p53 inhibitors, Rb and Mdm2, are cleaved by caspases during apoptosis,160-162 suggesting a positive self-regulation of
programmed cell death and close connection to key cell-cycle
regulators.
Whereas we do not entirely understand how p53 exerts its effects on cells, it is clear that the transcriptional activating function of p53 is a major component of its biological effects. Many p53 target genes have been identified, and those functions have been characterized. Cell-cycle arrest that is dependent on p53 requires transactivation of p21Waf1, GADD45, and cyclin G. Proapoptotic p53 target proteins include Bax, PIG genes, CD95, DR5 (a receptor for the death ligand TRAIL), IGF-BP3, Rpr (in Drosophila), Cdc42 (a Ras-like GTPase), Noxa (a Bcl-2 family protein), and p53AIP1.15,152,163-169 The mechanism of p53-induced apoptosis has been extensively studied and involves activation of the mitochondrial Apaf-1/caspase-9 pathway,170 death receptor signaling,50,171,172 and cleavage of downstream caspases.173 For example, cells expressing mutant p53 fail to induce CD95 and are less sensitive to drug-induced apoptosis.50,174 Independently of transcription, p53 may facilitate the transport of CD95 from Golgi stores to the membrane, leading to death receptor aggregation.171 However, in some cases CD95 is not essential for p53-mediated apoptosis, and p53-dependent up-regulation of CD95 does not induce apoptosis per se.175 An additional route by which p53 may signal apoptosis is through the production of ROS, which influence the mitochondrial membrane potential without involving cytochrome c release.173,176 In particular, the p53-inducible gene PIG3 shares homology with an NADPH-quinone oxidoreductase, which generates ROS. When overexpressed alone, PIG3 failed to initiate apoptosis, implying that other signals must be activated in parallel.177 Recently, p53 itself was shown to cause caspase activation in cell-free extracts from E1A/ras-transformed, but not normal, fibroblasts by a mechanism independent of transcription or presence of Bax or cytochrome c.178 Oncogene-dependent activation of caspases by p53 was also mediated by the c-Myc oncogene, a finding consistent with the requirement of caspase-9 and Apaf-1 in p53-dependent Myc-induced apoptosis.179 Thus, p53 can transduce apoptotic signals through protein-protein interactions, thereby modulating p53-dependent caspase activation. Another mechanism by which p53 promotes apoptosis is through activation of the Ras-like GTPase Cdc42, which activates the JNK1-induced phosphorylation of Bcl-2.168 Taken together, apoptosis mediated by or involving p53 consists of parallel or sequential activation of a set of different molecules and pathways that may need to act in concert to activate a full death response. NF- B activity is required for the induction of more than 150 genes involved in cell growth, differentiation, development, apoptosis,
and adaptive responses to changes in cellular redox balance (Figure
5). A wide variety of external stimuli
including cytokines, pathogens, stress, and chemotherapeutic agents can lead to the activation of NF-B.180 These stimuli induce
phosphorylation and subsequent degradation of IB inhibitory
proteins, thereby releasing NF-B proteins for translocation to the
nucleus to function as transcription factors.181
Phosphorylation of IB is mediated by a protein complex containing 2 kinases, IB kinase  and  (IKK-1 and IKK-2), and a noncatalytic
regulatory subunit called IKK.182 NF-B transcription
factors are heterodimer and homodimer complexes of related proteins
that contain a Rel homology domain involved in specific DNA binding,
protein dimerization, and nuclear import.180 The Rel
proteins predominantly found in mammalian cells consist of 2 transcriptionally inactive forms, NF-B1 (p50) and NF-B2 (p52),
and 3 transcriptionally active subunits known as RelA (p65), c-Rel, and
RelB.180
Different NF- NF- NF- Ceramide and cellular stress-induced apoptosis Ceramide, a sphingolipid-derived second messenger molecule, has been described as an important bioeffector molecule involved in cellular stress responses implicated in apoptosis, growth inhibition, and cellular differentiation (Figure 6). Stress stimuli such as TNF, CD95-L, oxidative stress, growth factor withdrawal, chemotherapeutic agents, ionizing or UV radiation, and heat shock induce an elevation in the endogenous levels of ceramide, and exogenous ceramide analogs mimic these biological responses in specific cell types.202-207
Hydrolysis of sphingomyelin, a main lipid in plasma membranes of mammalian cells, is the major source of ceramide. Sphingomyelin hydrolysis may occur via the action of sphingomyelin-specific forms of phospholipase C, termed sphingomyelinases (SMases), which are defined by their pH optima as neutral (nSMase) or acid (aSMase). These enzymes are activated in response to TNF and other cytokines. De novo synthesis via ceramide synthase may also lead to the generation of ceramide.203,205 The catabolic pathway for ceramide involves deacetylation by ceramidases to generate sphingosine, which is phosphorylated by sphingosine kinase to form sphingosine-1-phosphate (SPP). SPP in turn acts as a second messenger in cellular proliferation and survival induced by platelet-derived growth factor or serum. Previously, a model has been proposed in which the dynamic balance between the intracellular levels of ceramide and SPP is an important factor that determines whether a cell survives or dies. According to this model, stress stimuli such as TNF activate SMases, leading to increased intracellular ceramide levels and thus to increased cell death, whereas platelet-derived growth factor and other growth factors stimulate ceramidase and sphingosine kinase and elevate SPP levels, resulting in cellular survival and proliferation.208,209 Mechanisms by which ceramide induces multiple signaling pathways
involve the sequential activation of different kinases such as
ceramide-activated protein kinase (CAPK), phosphorylation of Raf-1, and
the MAPK cascade. Protein kinase C- Another metabolizing pathway for ceramide was proposed by Testi and coworkers.216 Ceramide can be shuttled to the Golgi complex, where it is converted to gangliosides. It was found that CD95 ligation or treatment with ceramide resulted in the accumulation of the ganglioside GD3, an event that was prevented by caspase inhibitors. Antisense oligonucleotides toward GD3 synthetase, which is localized in the Golgi complex, attenuated apoptosis, whereas overexpression of the wild-type enzyme was associated with massive cell death. Thus, GD3 ganglioside may be targeted to mitochondria, where it alters mitochondrial function and causes cell death during CD95-mediated apoptosis. While the role of ceramide for apoptosis induction, eg, through
death receptors, is highly controversial, there is a substantial evidence for a role of ceramide in the initiation of the apoptosis response by cytotoxic drugs and Despite these findings, much confusion remains about the role of endogenous ceramide in apoptosis. Whereas some publications place ceramide upstream of caspases,108,212,220-222 others suggest that it acts downstream of caspases, because it can be blocked by caspase inhibitors.223-226 A possible reason for the discrepancy on the role of ceramides may lie in methodologic problems. Ceramide production is mostly determined in assays using diacylglycerol kinase. In a recent investigation, no ceramide production in response to CD95 ligation could be detected using mass spectroscopy, whereas an apparent increase of ceramide was measured by the classical diacylglycerol kinase assay.227 It was suggested that lysates from apoptotic cells may stimulate diacylglycerol kinase activity directly, which then increases ceramide production. Thus, depending on the cell line used and the experimental setup, the effects of ceramide generation ranged from induction of apoptosis and cell-cycle arrest to proliferation and terminal differentiation.
Cytotoxic drugs have been developed for the treatment of leukemia and malignant tumors based on their capacity to inhibit cellular proliferation.228 While an overwhelming amount of data indicate that cytotoxic drugs induce and activate molecules of the apoptosis and cellular stress response pathway, a number of key questions are still open and unresolved. For example, the view that apoptosis represents the main mechanism by which tumor cells are killed by cancer therapy may not be universally true.229,230 Problems in identifying apoptosis signaling as a key event may be related to the assay used to detect drug-induced cell death. For example, cells that have received sufficient DNA damage to be unable to proliferate may die because of mitotic disaster, which is not detected in apoptosis assays but only in clonogenicity assays. Key elements of the cell death pathway are closely linked to other complex signaling systems such as the DNA damage response and cell-cycle control, which complicates the identification of individual compounds in the clinical setting.231,232 Most importantly, while in vitro assays have convincingly demonstrated that deregulated expression of apoptosis-mediating molecules may confer drug resistance,17,53 results of clinical studies in patients are less clear. Mutations of caspases are rarely found in tumors, although these molecules are the crucial effectors of the apoptosis response and would be ideal targets for mutations providing a survival advantage for tumor cells. Taken together, research on regulation of apoptosis, growth arrest, and DNA repair initiated by the cellular stress response has provided a detailed insight into fundamental cellular mechanisms with widespread clinical implications. Given the importance of cell death, including apoptosis as one possible outcome of the stress response in cells treated by cytotoxic drugs, further studies are required to identify the role of individual regulators of stress signaling and cell death for sensitivity to anticancer therapy. These will include analysis of gene expression profiles, novel proteomic approaches, as well as functional in vitro and in vivo studies in malignant cells from patients undergoing cancer therapy.
We apologize to those whose work was not cited or discussed because of space limitations. We thank R. Zwacka for critical reading and V. Krok-Szwed for assistance in preparing the manuscript.
Submitted February 23, 2001; accepted June 26, 2001.
Supported by the Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, EU grant, Deutsche Leukämieforschungshilfe, and Sander Stiftung.
@ 2001 by The American Society of Hematologycharge
Reprints: Klaus-Michael Debatin, Universitäts Kinderklinik, Prittwitzstr 43, D-89075 Ulm, Germany; e-mail: klaus-michael.debatin{at}medizin.uni-ulm.de.
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Abstract
Introduction
/
, JNK, and NF-
