hangInhibition of the non homologous end joining process in the context of hypoxic tumor cells

Introduction

In addition to surgery, cancer treatment is based on radiotherapy and targeted/non-targeted chemotherapy or both. Radiotherapy as well as most of the non-targeted drugs provoke the formation of DNA damage including oxidized or alkylated nucleotides, single-strand breaks (SSBs) and double-strand breaks (DSBs). Amongst DNA damage, DSBs are considered as a highly toxic lesion that, if improperly repaired, can induce genomic rearrangement (1). Consequently the repair of DSBs has been subject to a lot of investigations. In mammalian cells, DSBs trigger the DNA damage response (DDR), an interconnected network that tends to maintain cell viability and genomic stability (2,3). The DDR acts through checkpoint signaling and DNA damage repair (4). In mammalian cells the MRE11/RAD50/NBS1 (MRN) complex binds to DSBs and facilitates the activation of Ataxia Telangiectasia Mutated (ATM), the key phosphatidylinositol 3-kinase protein kinase-like (PI3KK) in the DDR (5) (Table 1). At the break site ATM autophosphorylation allows its activation to subsequently phosphorylate a large number of substrates in the chromatin surrounding (6). In addition to ATM, two other members of the PI3KK family, ataxia telangiectasia and Rad3 related protein (ATR) and DNA-dependent protein kinase (DNA-PK) play prominent roles in the DDR through the detection of DNA replication fork collapse and DSBs repair, respectively.

Table 1 Major factors involved in DNA strand breaks repair and damage signaling
Full table

DSBs repair is mainly dependent on the Non-homologous end joining (NHEJ) pathway that operates throughout the cell cycle (2,4,7-9). In contrast, the minor pathway, homologous recombination (HR), is active only during the S and G2 phases in which the sister chromatids are available to allow recombination processing. The balance between NHEJ and HR pathways is a prerequisite for efficient DSBs repair and relies on at least three factors: temporal control of proteins recruitment and modifications (10,11), chemical complexity of the breaks and chromatin conformation (12-14). Moreover a cross-talk between DNA-PKcs and ATM leads to a coordinated regulation of DSBs repair by NHEJ and HR (15).

Thus, the inhibition of DDR at the level of signaling and/or DNA damage repair by chemical compounds represents an area of research with the ultimate goal of sensitizing tumor cells to the treatment (16-19). Since the NHEJ pathway is under the control of DNA-PK, various compounds were selected to inhibit its activity. Interestingly, pharmaceutical companies did not take an interest in the research for DNA repair inhibitors since they favor the search for drugs that directly affect tumor cells or microenvironment. Recently, a renewed interest about DNA repair inhibitors was based on the killing effect of PARP inhibitors of BRCA1- and BRCA2-defective tumors (20-23). This example of an efficient monochemotherapy against solid tumors partially defective in DNA repair is reminiscent of the synthetic lethality mechanism (24-26).

Although DNA repair inhibitors are now in phase I/II trial, few of them being in phase III, one should keep in mind that tumor cells partly grow under hypoxia. The abnormal vasculature of tumors is considered as the most important contributor to the development of both chronic and acute hypoxia in the majority of solid tumors. Chronic hypoxia, or even anoxia in solid tumors is the consequence of abnormally long intravascular erythrocyte transit times. It is interesting to note that clinical evidence suggest that intra-tumoral hypoxia correlates with cell resistance to therapy as well as an aggressive behavior of the tumor leading to poor patient prognoses (27,28). A key regulator of the cellular response to hypoxia is the accumulation of the transcription factor hypoxia-inducible factor (HIF) which induces the expression of numerous target genes leading to cellular adaptation (29-31). Recent studies have reported diminished DNA repair capacities and increased mutagenesis in mammalian cells under hypoxic conditions (32-34). The NHEJ repair activity is affected in hypoxic cells and this short review summarizes the cross-talk between NHEJ and HIF pathways in the light of pharmacological inhibition of NHEJ in cancer therapy.

Hypoxic stress response and its impact on DNA repair

States of chronic hypoxia and transient hypoxia occur within solid tumors. Cells under chronic hypoxia are located beyond the diffusion limit of oxygen from a blood vessel (about 100 µm) whereas transient hypoxia corresponds to local oxygen depletion. Tumor adaptation to hypoxic stress occurs through modifications of its metabolism and induction of neovascularization. Oxygen concentrations of less than 0.02% (0.15 mmHg) render cells more resistant to killing by ionizing radiation by a factor of 2-3 (35). This stress response is controlled by HIF that binds to the cis-acting highly conserved consensus sequence 5'-G/ACGTG-3' referred as hypoxia response elements (HRE). The binding of HIF on HRE leads to increased expression of target genes involved in different pathways such as survival, glucose transport, glycolysis, angiogenesis, motility, basement membrane integrity and other functions (29,30,36). HIF is comprised of α- and β-subunits (37) with three HIFα isoforms reported to date, HIF-1α and HIF-2α being the best characterized. HIF-1α, the most ubiquitously expressed isoform, and HIF-2α regulate the expression of overlapping but non-identical genes (38,39). HIFα subunits are mainly targeted for normoxia-dependent degradation by the proteasomal system, whereas HIFβ subunits are constitutively expressed in most cells, HIF-1β/ARNT being the best characterized (29-31). Therefore, HIF activity is exquisitely dependent on the limiting expression of α subunit. Under normoxia HIFα subunits are hydroxylated by a family of prolyl hydroxylases (PHDs) (40-43) facilitating interaction with the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex (44). Then, Hifα is targeted for ubiquitin-dependent degradation leading to a low level of protein content. Under hypoxic stress, the PHDs are inhibited leading to the stabilization of HIFα that translocates to the nucleus allowing its heterodimerization with HIF-1β/ARNT. The HIF heterodimer bound to HRE in an association with transcriptional coactivators as CBP/p300 activates a variety of hypoxia-responsive genes. HIF dependent transcriptional regulation contributes to the adaptive response to hypoxic conditions by upregulating more than 100 genes (45).

HIF-1 is overexpressed in many human cancers and correlates with poor prognosis outcome (29). This is consistent with studies demonstrating that tumor cells containing constitutively high levels of Hif1α were more resistant to both chemotherapy and radiotherapy (46-49). In most of these cases, overexpression is the consequence of a constitutive stabilization of the protein by hypoxia. However, there is increasing evidence demonstrating that a number of non-hypoxic stimuli such as genetic alterations that activate oncogenes and inactivate tumor suppressor genes or growth factors signaling are also highly capable of turning this transcription factor on (36). Accordingly, HIF-1 represents an attractive target for the development of pharmacological inhibitors (28,50,51).

The impact of hypoxic stress has also been tested on DNA repair genes expression. After UVB irradiation, HIF-1 modulates the expression of XPC and XPD, two proteins of the nucleotide excision repair complex, with an increase of repair during the late phase of UV photoproduct removal (52). However, using an host-cell reactivation assay for repair of UV-damaged plasmid DNA, contradictory results of the effect of hypoxia on nucleotide excision repair were reported (53,54). Mismatch repair (MMR) which maintains genomic integrity by correcting replication errors is down-regulated under hypoxia through an epigenetic control (55-57). The consequence of this inhibitory effect is reminiscent to genomic instability in tumor cells grown under hypoxia. The recombination pathways are also affected by HIF-1 expression. HR repair proteins such as RAD51, BRCA2, and BRCA1 are compromised under hypoxic conditions (58-63). Contradictory results were reported on the expression of NHEJ proteins under hypoxia. Gene expression studies showed downregulation of mRNA encoding NHEJ proteins following chronic hypoxia but without change in protein content (62). In contrast under acute hypoxia an up-regulation of Ku70 expression and DNA-PKcs was reported as well as a direct interaction between DNA-PKcs and HIF1α (64,65). Very recently, an overexpresssion of Ku70/Ku80 proteins under the control of HIF-1 induction was reported (66). Then almost all of the DNA damage repair functions are repressed under hypoxia leading to cell sensitivity to therapy in contrast to the NHEJ pathway which is up-regulated (Figure 1). Under hypoxia, not only the expression of DNA-PK is enhanced but also its activity (67). DNA-PK is activated by mild hypoxia conditions (1% O₂) while more severe hypoxia (0.1% O₂) also activates ATM and ATR, two essential building blocks of the DNA DSBs signaling pathway. Hypoxia activates DNA-PK in the absence of DSBs in accordance with a study showing that activation of ATM in hypoxic cells arises independently of the MRN complex (68). Activation of DNA-PK or ATM could be triggered by stable association of single repair factors with chromatin in the absence of DNA lesions per se (69,70). Indeed, the DNA-PKcs autophosphorylation on S2056 was initiated by histone acetylation in response to hypoxia (67). These results illustrate the possibility of a non canonical DNA-PKcs activation which may be reminiscent to its activation under low salt conditions in the absence of Ku70/Ku80 (71).

Figure 1 Hypoxia regulates DNA repair genes expression and reciprocally.

NHEJ pathway and its pharmacological inhibition

Hypoxia can regulate DSBs repair through HR and NHEJ. In mammalian cells, NHEJ is the predominant repair pathway for DSBs which ligates the two DNA ends together with minimal end processing (72,73). NHEJ consists of at least two genetically and biochemically distinct sub-pathways: (I) a main canonical DNA-PK end-joining pathway named classical NHEJ (C-NHEJ) (7-9) and (II) an alternative or backup NHEJ end-joining pathway (Alt-NHEJ) (74-76).

C-NHEJ proceeds via at least three steps: (I) break recognition; (II) processing of the damaged DNA ends to remove non-ligatable groups; and (III) ligation to restore strand continuity. The prerequisite event for all the subsequent steps is the binding of the Ku70/Ku80 heterodimer to DNA ends (77). Live cell imaging studies following laser micro-irradiation indicate that core NHEJ components are independently recruited to Ku-bound DSBs (78), including the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XLF and the preassembled XRCC4/DNA Ligase IV complex (79). The DNA-PK holoenzyme is formed when DNA-PKcs binds to Ku at DSB ends and provides DNA ends recognition and protection activities followed by bridging the ends, associated with serine/threonine protein kinase activity (80). The kinase activity of DNA-PK is required for DSBs repair. In addition, DNA-PK conformational change mediated by autophosphorylation is necessary for the dissociation of the DNA-PKcs subunit from DNA ends and also for the activation of end-processing enzymes, such as the Artemis nuclease (81-83). Ligation requires the concerted action of LIG4, XRCC4 and XLF, the latter promoting re-adenylation of LIG4 (84,85). At a later stage in the C-NHEJ process, this molecular machinery is released from the re-ligated DNA.

Alt-NHEJ, detected only when C-NHEJ is compromised, exhibits a slower process (86) and produces deletions often accompanied by microhomology at the repair junction (76,87,88). This pathway relies on factors different from those involved in the C-NHEJ, such as poly (ADP-ribose) polymerase-1 (PARP-1), X-ray cross complementing factor 1 (XRCC1), DNA ligase III, polynucleotide kinase (PNK), or Flap endonuclease 1 (75,86,89-92). PARP-1 is a major sensor of DNA SSBs and participates to the core repair complex involving XRCC1-ligase III but also recognizes DSBs with very high affinity. Recently, the MRN complex has been implicated in the Alt-NEHJ mechanism (93-98). Alt-NHEJ is repressed under normal growing conditions by the Ku70/Ku80 heterodimer (86,99-104). This alternative NHEJ pathway may be particularly relevant to genomic instability associated with tumor development (105-108).

Since DDR defects are a common feature of tumor cells, the development of pharmacological inhibitors of DNA-PK, ATM and ATR, highlighted opportunities and challenges in cancer therapy (19,109). The core C-NHEJ complex was investigated as a target in relation with its involvement in radio- and chemoresistance of tumor cells (110,111). As soon as DNA-PK was described as the central partner of C-NHEJ (112-116), the search for specific inhibitors was undertaken (117). In addition, DNA-PK has been implicated in the repair of chlorambucil-induced cross-links, because increased DNA-PK activity in CLL cells correlates with clinical resistance to chlorambucil (118,119). Indeed, inhibitors of DNA-PKcs kinase activity have been shown to have efficacy in human cells (120,121) in line with the development of new compounds (109,122-124). In addition to these small chemical compounds, basically ATP-competitive inhibitors, antibody based inhibitors could also be effective as DNA-PK inhibitors. Recently, a DNA-PK specific antibody modified fragment ScFv18-2 was reported to decrease DNA-PK phosphorylation which correlates to radiosensitization (125). However, the therapeutic efficacy of targeting DNA-PK will depend in part on DNA-PK expression in tumor versus normal cells.

Among the different possibilities to inhibit NHEJ, the Ligase IV may be a better pharmacological target than DNA-PK itself, since the inhibition of the ligation step will not allow the Alt-NHEJ pathway to proceed due to the remaining Ku binding to DNA. Thus, the ligation complex was also investigated as an alternative strategy and inhibitors have been selected (126,127). However, the inhibitory effect should be complete since low levels of DNA ligases III and IV were sufficient for effective NHEJ which limits the potency of such alternative strategy (128). A different strategy is illustrated by the use of non specific kinase inhibitors such as KU-0060648 which is a potent dual inhibitor of DNA-PK and PI-3K. In relation with the role of the kinases in DSBs repair and the promotion of cell proliferation, KU-0060648 exhibits a direct effect but the toxicity is enhanced in cells treated with topoII inhibitors (120). At last, indirect approaches such as the use of short double-stranded DNA, Dbaits, have been shown to sensitize xenografted tumors to radiotherapy, not by inhibiting the kinase activity of DNA-PK, but by acting through the induction of “false” DNA damage signaling (129-131).

Whatever the NHEJ component selected as target, the inhibitors are mainly used as radio- or chemosensitizers in order to block DNA repair resulting in increased cell death. Such approaches enhance sensitivity to treatment, although they do not provide selectivity against cancer cells as they increase the radiosensitivity or chemosensitivity of normal cells as well. However, this drawback is related to chemotherapy since radiotherapy targets a defined tissue volume. Moreover, DDR defects are commonly associated to tumor cells with the loss of DNA repair processes resulting in genomic instability. Consequently such deficiency allows to potentially achieve selective antitumour activity through the inhibition of an essential DNA repair pathway such as NHEJ. The toxic activity of DDR inhibitors used in monochemotherapy was illustrated by the synthetic lethality obtained with PARP-1 inhibitors in BRCA1/BRCA2 deficient tumours which has raised the recent interest in the DDR modulation field. Despite a high level of expression of Ku and DNA-PK_CS, an up-regulation of DNA-PK_CS was reported in tumors or IR-resistant cell lines, suggesting a role in tumor growth and survival (132-135). Indeed, up-regulation of DNA-PK activity was shown to impair apoptosis in B-cell chronic lymphocytic leukemia (136). Moreover, in colorectal mismatch repair-deficient tumor cells, mutations in genes involved in DDR and DNA repair, including DNA-PK_CS, have been reported (137). Taken together, all these alterations in DNA-PK expression or activity suggest that the consequences of its inhibition should be useful against tumors in line with a mechanism of toxicity based on the synthetic lethality process. However, in tumor tissues, the expression of DNA-PK shows intratumor heterogeneity, suggesting difficulty in predicting the radio- or chemo-sensitivity of the tumor as well as when a DNA-PK inhibitor might be beneficial (138).

HIF regulation by PI3KK recruited at DNA damage sites

HIF activity is regulated in two major ways. The first relies on hydroxylation-dependent degradation/inactivation of HIFα while the second involves oxygen-independent factors in a cell type-specific manner such as epidermal growth factor receptor (EGFR), heat-shock protein 90, phosphatidylinositol 3-kinase/AKT and MAPK, cyclooxygenase-2 activity (31,139-141). Interestingly, HIF-1α is also regulated by members of the PI3KK family, ATM, ATR and DNA-PK (Figure 1).

ATM protein deficiency correlates with an increased expression and activity of HIF-1α protein (142,143). Similarly, the inhibition of ATM in a mouse model suppressed the induction of senescence and leads to increased tumor size and invasiveness (144). Under hypoxia ATM phosphorylates HIF-1α at Ser696 site, which is required for its stability through putative posttranslational modifications such as sumoylation (143). Hereafter, ATM participates in conjunction with several other factors to the maintenance of an elevated mTORC1 activity in hypoxic tumors.

Hypoxia is known to induce a replication-associated damage response. For example, severe hypoxia induces S-phase arrest resulting in regions of single-stranded DNA at stalled replication forks and the activation of ATR (145). Loss of ATR results in a further loss of viability in S-phase cells under hypoxic conditions (146). Inhibition of ATR expression and activity inhibited cell survival upon hypoxic conditions (147). Under severe hypoxic conditions (0.1% O₂), ATR is activated at early time points and this cellular stress response favors hypoxia adaptation by up-regulating the expression of both HIF-1α and HIF-1β/ARNT subunits, therefore contributing to cell adaptation to hypoxia (147). The mechanism of ATR dependent regulation of HIF-1α accumulation during hypoxia is at the stage of HIF-1α translation.

DNA-PK also participates to HIF regulation since the level of HIF-1α accumulation upon hypoxia is decreased in DNA-PK deficient cells (67). Similarly, the DNA-PK kinase activity, NU7026, provokes a decreased in HIF-1α content. Moreover, activated DNA-PK which is strictly dependent on Ku70/80 is able to regulate HIF-1α accumulation by interfering with the mechanisms protecting HIF-1α from nuclear degradation and subsequent increased expression of HIF-1 target genes (67).

Thus, the hypoxic accumulation of HIF-1 is positively regulated by ATM, ATR and DNA-PK that initiate cellular stress responses when either genome integrity, mRNA translation, or nutrient availability is compromised.

Conclusions and perspectives

The DDR (DNA damage response) induced during hypoxic stress has recently emerged as an important signaling pathway that allows cells to withstand modifications in environmental conditions. In contrast to other DNA-repair pathways, which were downregulated, leading to genetic instability (33), ATR, ATM and DNA-PK remained expressed and activated. Interestingly, the mechanism of hypoxia-induced activation of both DNA-PK and ATM is distinct from that of the DNA DSBs and stems on chromatin modifications. Taken together, activation of these three PI3KK during hypoxic stress allows HIF-1α accumulation in the nucleus. This regulation by non-hypoxic effectors influence HIF function, directly or indirectly, at different stages of its activation.Thus, the correlated regulation of PI3KKs with HIF-1 could contribute to therapy resistance in hypoxic tumor cells, and provides new evidence for developing therapeutic strategies enhancing the efficacy of cancer therapy in hypoxic tumor cells. In addition, hypoxia results in ATM-dependent phosphorylation of HIF-1α and mediates downregulation of mTORC1 signalling (143). Hereafter, inhibition of DNA-PK and ATM not only radiosensitize tumor cells but also interfere with HIF dependent regulation. Moreover, the use of NHEJ inhibitors alone could induce cell death through synthetic lethality, since DNA repair pathways and signaling are altered in tumors, most of them resulting of a mutated MMR pathway.

However, targeting the NHEJ pathway may be therapeutically inefficient or lead to unexpected results based, at least, on the following points:

(I) the dual effect on NHEJ and HIF activities presupposes drug delivery to the hypoxic region; (II) the expression of DNA-PK shows intratumor heterogeneity; (III) inhibition of DNA-PK may increase HR activity but also the Alt-NHEJ pathway; (IV) inhibition of DNA-PK is not expected to be specific towards tumor cells; (V) inhibition of DNA-PK may affect its function in regulatory mechanisms out of the canonical DSBs repair process (148). For instance DNA-PK plays a role in the USF-1-mediated transcriptional regulation of lipogenic genes during fasting/feeding (149). DNA-PK and Ku play other roles outside the nucleus (150) and may phosphorylate cytoplasmic targets involved in cellular signaling pathways (151). In addition, Ku has been reported as a moonlighting protein, displaying new functions in the cytoplasm or at the membrane level (152,153). Consequently, the potential effect of DNA-PK inhibitors with high or low specificity deserve to be investigated in vivo with tumor xenografts in order to take into account the complexity of these regulatory networks.

Acknowledgments

I acknowledge Drs P Calsou and C Muller from my previous team.

Funding: I acknowledge the financial support from ‘Ligue Nationale Contre le Cancer’ and Cancéropole GSO (Toulouse, France).

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (David J. Chen and Benjamin P.C. Chen) for the series “DNA Damage and Repair” published in Translational Cancer Research. The article has undergone external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.3978/j.issn.2218-676X.2013.05.01). The series “DNA Damage and Repair” was commissioned by the editorial office without any funding or sponsorship. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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