tissue homeostasis is characterized by the balance between proliferation and cell growth on one side and cell death on the other side . in response to stressful stimuli , however , in cancer cells activation of pathways that favor cell survival instead of cell death under stressful conditions may contribute to tumorigenesis . in addition , this adaptive stress response promotes the development of acquired resistance , since current treatment approaches such as chemotherapy and irradiation trigger cellular stress pathways , and thus , initiate the activation of survival cascades and anti - apoptotic mechanisms . apoptosis or programmed cell death is the cell 's intrinsic death program that regulates various physiological as well as pathological processes and that is evolutionary highly conserved . hence , further insights into the molecular mechanisms of how cellular stress signals trigger anti - apoptotic mechanisms and how this contributes to tumor resistance to apoptotic cell death are expected to provide the basis for a rational approach for the development of new molecular targeted therapies . there are two major apoptosis signaling pathways , that is , the death receptor ( extrinsic ) pathway and the mitochondrial ( intrinsic ) pathway . under most circumstances , activation of either pathway eventually leads to proteolytic cleavage and thus activation of caspases , a family of cysteine proteases that act as common death effector molecules . accordingly , caspases are responsible for many of the biochemical and morphological hallmarks of apoptotic cell death by cleaving a range of substrates in the cytoplasm or nucleus . ligation of death receptors of the tumor necrosis factor ( tnf ) receptor superfamily such as cd95 ( apo-1/fas ) or trail receptors by their corresponding natural ligands , that is , cd95 ligand or trail , results in the recruitment of caspase-8 into a multimeric complex at the plasma membrane , the death - inducing signaling complex ( disc ) [ 6 , 7 ] . this in turn leads to caspase-8 activation , which can then directly cleave downstream effector caspases such as caspase-3 . alternatively , caspase-8 can promote outer mitochondrial membrane permeabilization by cleaving bid , a bh3-only protein that translocates to mitochondria upon cleavage and causes cytochrome  c release . the mitochondrial pathway is initiated by the release of apoptogenic factors such as cytochrome c , apoptosis - inducing factor ( aif ) second mitochondria - derived activator of caspase ( smac)/direct iap binding protein with low pi ( diablo ) or omi / high temperature requirement protein a ( htra2 ) from the mitochondrial intermembrane space into the cytosol . the release of cytochrome c into the cytosol triggers activation of caspase-3 via the formation of a large cytosolic complex , which is called the apoptosome and consists of cytochrome c , apaf-1 , and caspase-9 . smac / diablo or omi / htra2 promotes caspase activation by binding to inhibitor of apoptosis ( iap ) proteins and thereby disrupts the interaction of iaps with caspase-3 or -9 [ 9 , 10 ] . therefore , cancer cells react to cellular stress signals by mounting an anti - apoptotic response , which enables cancer cells to evade apoptotic cell death and ensures cell survival . a wide range of stress signals has been identified , which may evoke a cell survival program in case of sublethal damage , while cell death is usually initiated if the damage is too severe , that is , starvation , hypoxia , dna damaging drugs , irradiation , er stress , and reactive oxygen species just to name a few . the molecular mechanisms that initiate cell death upon cellular stress stimuli have often not exactly been identified and likely depend on the individual stimulus . for example , following exposure to genotoxic substances , damage to dna or to other critical molecules is considered to be a common initial event which is then transmitted by the cellular stress response to the activation of cellular effector systems such as the apoptotic machinery     . various stress - inducible molecules , for example , jnk , mapk / erk , nf-b , or ceramide have been implicated in propagating the apoptotic signal     [ 1315 ] .   besides caspase - dependent and caspase - independent apoptosis , additional non - apoptotic modes of cell death also exist and have gained increasing attention over the last years , including necrosis , autophagy , mitotic catastrophe , and lysosomal cell death [ 16 , 17 ] . while resistance to these cell death modalities can also contribute to evasion of cell death under stress conditions , the discussion of these alternative modes of cell death is beyond the scope of this review . a characteristic feature of human cancers is the evasion of apoptosis in response to stress stimuli , which contributes to both tumorigenesis and treatment resistance . in principle , cell death pathways can be blocked at different levels of the signaling cascade by upregulation of anti - apoptotic proteins and/or by downregulation or dysfunction of proapoptotic molecules . examples of altered apoptosis signaling pathways that contribute to stress resistance in human cancers will be discussed in the following paragraphs ( figure 1 ) . death receptors are part of the tumor necrosis factor ( tnf ) receptor gene superfamily , which comprises more than 20   proteins , for example , cd95 ( apo  1/fas ) , trail receptors , and tnf receptor 1 ( tnfri )     [ 7 , 19 ] . death receptors exert many different biological functions , including the regulation of cell death and survival , differentiation , and immune regulation     [ 7 , 19 ] . members of the tnf receptor family share a characteristic cytoplasmic domain called the  death domain ,  which is pivotal for transducing the death signal from the cell 's surface to intracellular signaling pathways     [ 7 , 19 ] . signaling via death receptor can be impaired in human cancers via downregulation of receptor surface expression as part of an adaptive stress response . for example , in chemotherapy - resistant leukemia or neuroblastoma cells , downregulation of cd95 expression was identified as a mechanism of acquired drug resistance [ 20 , 21 ] . for the apoptosis - inducing trail receptors trail - r1 and trail - r2 , abnormal transport from intracellular stores such as the endoplasmatic reticulum to the cell surface rendered colon carcinoma cells resistant to trail - induced cell death     . further , membrane expression of death receptors can be reduced by epigenetic changes such as cpg - island hypermethylation of gene promoters in response to stress signals     [ 23 , 24 ] . abnormal expression of decoy receptors presents an alternative mechanism of resistance to trail- or cd95-induced apoptosis . to this end , the decoy receptor 3 ( dcr3 ) , which counteracts cd95-mediated apoptosis by competitively binding cd95 ligand , was shown to be overexpressed in lung carcinoma   or colon carcinoma and in glioblastoma     [ 25 , 26 ] and trail - r3 ; a decoy receptor for trail was reported to be expressed at high levels in gastric carcinoma     . in addition , anti - apoptotic proteins with a death effector domain ( ded ) such as cellular flice - inhibitory protein ( cflip ) and phosphoprotein enriched in diabetes/ phosphoprotein enriched in astrocytes-15  kda ( ped / pea-15 ) can be aberrantly expressed upon cellular stress     [ 28 , 29 ] . for example , high oxygen tension ( hyperoxia ) has been reported to lead to upregulation of cflip , which inhibited apoptosis during hyperoxia by suppressing both extrinsic and intrinsic apoptotic pathways , the latter via inhibition of bax . because of their sequence homology to caspase-8 , both cflip and ped can be recruited into the death - inducing signaling complex ( disc ) upon receptor ligation instead of procaspase-8 , thereby preventing caspase-8 activation     [ 28 , 29 ] . moreover , the expression of caspase-8 or its function is impaired by genetic or epigenetic mechanisms in various cancers . for example , caspase-8 mutations were identified in some tumors , that is , in colorectal and head and neck carcinomas , although the overall frequency is low     [ 31 , 32 ] . alternative splicing of intron 8 of the caspase-8 gene resulting in the generation of caspase-8l , a catalytically inactive splice variant presents another mechanism of caspase-8 inactivation     [ 34 , 35 ] . epigenetic silencing secondary to hypermethylation of regulatory sequences of the caspase-8 gene occurs in various tumors , for example , neuroblastoma , malignant brain tumors , ewing tumor , retinoblastoma , rhabdomyosarcoma , or small lung cell carcinoma     [ 33 , 3639 ] . furthermore , phosphorylation of caspase-8 on tyrosine 308 by , for example , src has been shown to interfere with its proapoptotic activity     . the bcl-2 family of proteins consists of both anti - apoptotic proteins , for example , bcl-2 , bcl - xl , and mcl-1 , as well as proapoptotic molecules such as bax , bak , and bh3 domain only molecules . there are currently two models to explain the activation of bax and bak by bh3-only proteins . the direct activation model holds that bh3-only proteins , which act as direct activators such as bim and the cleaved form of bid ( tbid ) , bind directly to bax and bak to trigger their activation , while bh3-only proteins that act as sensitizers , for example , bad , bind to the prosurvival bcl-2 proteins     . according to the indirect activation model , bh3-only proteins activate bax and bak in an indirect fashion by engaging the multiple anti - apoptotic bcl-2 proteins that inhibit bax and bak , thereby releasing their inhibition on bax and bak     [ 42 , 43 ] . regardless of the exact mode of bax and bak activation , the ratio of anti - apoptotic versus proapoptotic bcl-2 proteins rather than the expression levels of one particular molecule of the bcl-2 family regulates apoptosis sensitivity . an increase in the ratio of anti- to proapoptotic bcl-2 proteins has been detected in various cancers and has been correlated to tumor cell survival and apoptosis resistance . more recently , bcl-2 has also been implicated in the regulation of the intracellular redox status . bcl-2 localizes to mitochondrial membranes as well as the endoplasmatic reticulum and the nuclear envelope , which are all sites of ros production . while bcl-2 has initially been described as an anti - oxidant because of its inhibitory effect on h2o2-induced lipid peroxidation     , there is also evidence that bcl-2 may promote a prooxidant intracellular milieu . accordingly , ectopic expression of bcl-2 resulted in an elevated constitutive level of superoxide anion and intracellular ph in leukemia cells     . conversely , reduction of intracellular superoxide sensitized bcl-2-overexpressing tumor cells to apoptotic stimuli independent of the mitochondria     . these findings provide a link between oncogene - mediated alterations in the intracellular redox status and cell survival .   besides bcl-2 ,   also cytochrome c has been implicated in the redox regulation of apoptosis . once cytochrome c is released from mitochondria into the cytosol , it triggers formation of the cytochrome c / apaf-1/caspase-9-containing apoptosome , which in turn lead to activation of caspase-9 and downstream effector caspases . there is recent evidence that also the redox state of cytochrome c is involved in the regulation of apoptosis . to this end , the oxidized form of cytochrome c ( fe(3 + ) ) has been reported to induce caspase activation via the apoptosome , while the reduced form of cytochrome c ( fe(2 + ) ) is unable to do so     [ 4951 ] . several mechanisms have been discussed to be responsible for this redox - mediated regulation of cytochrome c activity , including different affinities of the oxidized versus the reduced form of cytochrome c for binding to apaf-1 , different abilities of these cytochrome c forms to activate apaf-1 , or , alternatively , different affinities for other factors not belonging to the apoptosome . regardless of the exact mechanisms , this regulation of the redox state of cytochrome c opens the possibility of controlling the effector phase of apoptosis at a postmitochondrial level .   besides these genetic alterations in bcl-2 family proteins , impairment of mitochondrial apoptosis may also occur at the postmitochondrial level . for example , expression level or activity of apaf-1 may be reduced due to promoter hypermethylation or loss of heterozygosity at chromosome 12q22 - 23 , which in turn leads to impaired assembly of a functional apoptosome     [ 5256 ] . moreover , tumor resistance to apoptosis may be caused by aberrant expression or function of  inhibitor of apoptosis iap proteins are a family of endogenous caspase inhibitors with eight human members , that is , xiap , ciap1 , ciap2 , survivin , livin ( ml - iap ) , naip , bruce ( apollon ) , and ilp-2     [ 10 , 57 ] . all iap proteins have at least one baculovirus iap repeat ( bir ) domain that is required for classification as iap family protein . this domain is also the region of the protein that mediates the interaction with caspases . among the iap family proteins , xiap exhibits the strongest anti - apoptotic properties and inhibits apoptosis signaling by binding to active caspase-3 and -7 and by preventing caspase-9 activation . the expression and function of iap proteins are tightly regulated by several mechanisms , among them is translational regulation . to this end , it is particularly interesting to note that xiap and ciap1 belong to the proteins , which are translated via an internal ribosome entry site ( ires ) . this unique property enables protein translation of these iap proteins even under cellular stress conditions when protein synthesis is usually shut down , for example , because of caspase - dependent breakdown of eukaryotic translation initiation factors coupled with activation of the double - stranded rna - activated protein kinase pkr . however , the mrnas encoding xiap or ciap1 protein contain very long 5 untranslated regions ( utrs ) , which are not amenable to a ribosome - scanning translation initiation mechanism and thus , require a cap - independent translation initiation mechanism , that is , ires - mediated translation . ires - mediated translation allows for the continued translation of xiap and ciap1 even under conditions where cap - dependent translation is inhibited such as cellular stress . in addition , ires - mediated translational regulation of xiap and ciap1 expression enables a rapid response to transient cellular stress conditions in order to delay cell death and ensure survival . of note , cellular stress signals , including low - dose irradiation , anoxia , serum starvation and chemotherapeutic drugs , have been reported to stimulate the ires activity of xiap or ciap1     [ 6366 ] . this is in line with the concept that such stress signals promote cell survival under stress conditions , at least in part , via ires - mediated upregulation of anti - apoptotic proteins . evasion of apoptosis is one of the hallmarks of human cancers that promote tumor formation and progression as well as treatment resistance . cellular stress signals can contribute to evasion of apoptosis by activating anti - apoptotic and cell survival programs that ultimately block cell death . this interference with proper apoptosis signaling under stress conditions can occur at different points of the apoptosis signaling network , for example , within the death receptor or the mitochondrial pathway or at the postmitochondrial level . whether or not cellular stress eventually engages cell survival or cell death programs also depends on the type and strength of the stress stimulus as well as the cell type . a better understanding of the molecular mechanisms of this interplay between the cellular stress response and anti - apoptotic programs is expected to yield novel molecular targets for therapeutic interventions . the aim is to prevent protective responses in order to maximize the antitumor activity of anticancer treatment approaches .