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Carcinogenesis Advance Access originally published online on May 27, 2004
Carcinogenesis 2004 25(10):1787-1793; doi:10.1093/carcin/bgh196
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Carcinogenesis vol.25 no.10 © Oxford University Press 2004; all rights reserved.

COMMENTARY

The adaptive imbalance to genotoxic stress: genome guardians rear their ugly heads

Lorne J. Hofseth

Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA

Email: hofseth{at}cop.sc.edu


   Abstract
Top
 Abstract
Introduction
 p53 adaptation
 DNA repair adaptation
 Cell cycle checkpoint adaptation
 Apoptosis adaptation
 Antioxidant adaptation
 Carcinogen metabolizing...
 Conclusions and perspectives
 References
 
An adaptive response of the genome-protection machinery occurs in cells exposed to genotoxic stress. This machinery includes the p53 and retinoblastoma protein pathways, which are not mutually exclusive from other adapting machinery including DNA repair, cell cycle checkpoints, apoptosis and endogenous metabolizing and antioxidant enzymes. The adaptive changes occur in chronic inflammation and in cigarette smokers associated with a high cancer risk, and are an attempt to keep cells healthy. However, there is increasing evidence that this response may have deleterious effects. Here, key pathways that adaptively respond to genotoxic stress are reviewed and mechanisms by which this response may have pro-carcinogenic implications are discussed.

Abbreviations: BER, base excision repair; Gadd, growth arrest and DNA damage-inducible; GPx, glutathione peroxidase; NO, nitric oxide; pRb, retinoblastoma protein; SOD, superoxide dismutase


   Introduction
Top
 Abstract
 Introduction
p53 adaptation
 DNA repair adaptation
 Cell cycle checkpoint adaptation
 Apoptosis adaptation
 Antioxidant adaptation
 Carcinogen metabolizing...
 Conclusions and perspectives
 References
 
When a cell is exposed to genotoxic stress through viral, chemical or physical means, an adaptive response occurs involving an adjustment in the levels and/or activity of its genome-protecting protein machinery. These proteins are involved in DNA repair, cell cycle checkpoints and apoptosis. Some have free radical scavenging properties (Table I). This is a survival mechanism aimed at maintaining good cellular health. The following is a discussion of the current knowledge of proteins and pathways that adaptively respond to genotoxic stress. Highlighted at the end of each section is the emerging evidence that these adaptive responses can paradoxically generate genotoxic stress and exacerbate carcinogenesis. A summary of these pro-carcinogenic mechanisms of genome guardian adaptive responses is provided in Table II.


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  		Table I. Examples of mammalian genome protecting proteins that are induced in vitro and in vivo by genotoxic stress

 

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  		Table II. Examples of pro-carcinogenic characteristics of genome guardians

 

   p53 adaptation
Top
 Abstract
 Introduction
 p53 adaptation
DNA repair adaptation
 Cell cycle checkpoint adaptation
 Apoptosis adaptation
 Antioxidant adaptation
 Carcinogen metabolizing...
 Conclusions and perspectives
 References
 
The p53 protein is a key tumor suppressor protein that lies at the crossroads of cellular stress response pathways (1,2). Through these pathways resulting in cell cycle checkpoint arrest, DNA repair, cellular senescence, differentiation, apoptosis and free radical generation, p53 facilitates the repair and survival of damaged cells or eliminates severely damaged cells from the replicative pool to protect the organism. This p53 adaptive response was first observed with UV (3) and {lambda}-IR (4,5), and has since been shown to occur with many other genotoxic stresses, including chronic inflammation (6).

For the most part, induction of p53 has a favorable outcome to the organism, and thus a primary focus for cancer treatment is the induction and stabilization of wild-type p53. However, this induction may not have favorable effects if there is an induction of a mutated form of p53. Proof-of-principle comes from mouse experiments where transgenic mice carrying mutant p53 have accelerated tumorigenesis (7–11). Interestingly, p53 mutant mice have an augmented p53 response to genotoxic stress (12). This leads to speculation that this may occur in patients with high cancer risk, chronic inflammatory (‘oxyradical overload’) diseases, because these patients have a high p53 mutation load (13,14) with inducible p53 (6). Interestingly, p53 has also been shown to transactivate genes involved in free radical formation (15,16). Although pro-oxidant states (17) are pro-apoptotic, they may have deleterious effects on the cell by generating damage in key cancer genes and proteins.

Another key tumor suppressor protein deserving attention here is the retinoblastoma protein (pRb). pRb levels have been shown to be elevated in colorectal carcinomas. This apparent paradox has been discussed previously (18). Also worth mentioning is the issue of pRb and its functional dependence on phosphorylation status (19). In a pRb hyperphosphorylated state, E2F transcription factors are released, which activates the DNA replication machinery and allows cell cycle progression. Therefore, a careful assessment of pRb phosphorylation status is necessary to rule out that the increase in pRb protein levels is not associated with a concomitant increase in pRb phosphorylation. If so, then this could explain the apparent transformation of this genome guardian to that of a pro-carcinogenic molecule.


   DNA repair adaptation
Top
 Abstract
 Introduction
 p53 adaptation
 DNA repair adaptation
Cell cycle checkpoint adaptation
 Apoptosis adaptation
 Antioxidant adaptation
 Carcinogen metabolizing...
 Conclusions and perspectives
 References
 
It has long been known that bacteria have an SOS response, in which DNA repair is induced following DNA damage (20,21). Although less robust, the repair machinery of mammalian cells can also adapt to genotoxic stress. For example, ß-polymerase and 3-methyl-adenine DNA glycosylase (AAG), two enzymes involved in base excision repair (BER), and O6-methylguanine-DNA methyltransferase, are inducible by genotoxic stress (22–24). More recently, studies have found the DNA repair machinery adaptively responds to oxidative and nitrosative stress, both in vitro and in vivo (25–29). This response is an attempt to repair DNA damage created by the genotoxic stress and maintain good cellular health. Evidence is now emerging that this response could have deleterious effects.

The pro-mutagenic consequences of DNA repair was first identified in the Escherichia coli SOS repair mechanism. In the early 1990 s, Xiao and Samson demonstrated that imbalanced BER could affect spontaneous mutation rates (30). Recent studies have shown that over-expression and an imbalance in mismatch repair proteins can lead to increased mutation rates (31,32). In mammalian cells, over-expression of specific BER enzymes generates chromosomal instability and may contribute to tumorigenesis (33,34). We have shown that there is an imbalance in BER enzymes in chronic inflammation and that this could generate microsatellite instability in patients with the high colon cancer risk, oxyradical overload disease ulcerative colitis (29).


   Cell cycle checkpoint adaptation
Top
 Abstract
 Introduction
 p53 adaptation
 DNA repair adaptation
 Cell cycle checkpoint adaptation
Apoptosis adaptation
 Antioxidant adaptation
 Carcinogen metabolizing...
 Conclusions and perspectives
 References
 
Genotoxic stress in cells leads to a temporary growth arrest. This pause, or cell cycle arrest, bides time for repair of damaged cellular DNA before DNA replication occurs. Critical molecules involved in cell cycle checkpoints are cyclins and their associated kinases (cyclin-dependent kinases). Negative regulators of cyclins and cyclin-dependent kinases can act as a braking mechanism and pause the cell in the G1, S or G2 phase of the cell cycle. The G1 delay allows for repair of damage before it is replicated. The S phase completion checkpoint, activated by stalled replication machinery and DNA damage, and the G2 checkpoint have a protective effect by allowing additional time for repair of DNA damage prior to entry into mitosis (35). p21Waf1/Cip1/Sdi1 is a key protein involved in both G1 (36) and G2 (37) cell cycle arrest. Gadd45 (growth arrest and DNA damage-inducible) is a key protein involved in a G2 cell cycle arrest (38). Both these proteins are inducible and have been shown to be elevated in chronic inflammation (6,39,40).

There is some evidence that expression of p21Waf1/Cip1/Sdi1 or Gadd45 has negative effects on genomic stability. Smith et al. (41,42) found a lack of Gadd45 resulted in an increased sensitivity to cell killing by UV radiation or cisplatin, indicating a possibility that over-expression of Gadd45 leads to reduced cell mortality with carcinogenic consequences. As a cell cycle checkpoint protein, p21Waf1/Cip1/Sdi1 plays a key role in tumor suppression. However, there is also evidence that p21Waf1/Cip1/Sdi1 has genome destabilizing and oncogenic functions (43). Similar to Gadd45, loss of p21Waf1/Cip1/Sdi1 renders cells sensitive to ionizing radiation (44). This loss also delays the onset of lymphoma in ATM-deficient mice (44). Other studies have reported that anti-sense knockdown of p21Waf1/Cip1/Sdi1 inhibits cyclin D complex assembly and growth factor-mediated cellular proliferation (45). Recently, Dong et al. (46) showed stimulation of proliferation with p21Waf1/Cip1/Sdi1 over-expression. Although some studies indicate a positive correlation of p21Waf1/Cip1/Sdi1 expression with a positive prognosis (47–52), other studies find a negative association between p21Waf1/Cip1/Sdi1 expression and prognosis (53–58). Several mechanistic studies could explain these observations of a pro-carcinogenic role for p21Waf1/Cip1/Sdi1. p21Waf1/Cip1/Sdi1 can generate endoreduplication, which is a doubling of DNA content due to an unscheduled round of DNA replication (59,60). Studies have also shown that following p21Waf1/Cip1/Sdi1-induced growth arrest, abnormal mitosis develops in tumor cells (61,62). Wild-type p21Waf1/Cip1/Sdi1 can also inhibit apoptosis and stimulate transcription of secreted factors with mitogenic and anti-apoptotic acitivites (43). These studies then highlight a pro-carcinogenic role for p21Waf1/Cip1/Sdi1 and a need to reassess the role of this protein as a genome protector.


   Apoptosis adaptation
Top
 Abstract
 Introduction
 p53 adaptation
 DNA repair adaptation
 Cell cycle checkpoint adaptation
 Apoptosis adaptation
Antioxidant adaptation
 Carcinogen metabolizing...
 Conclusions and perspectives
 References
 
Apoptosis can occur if a stress is so genotoxic that repair is not an option. Insufficient apoptosis can manifest as cancer or autoimmunity, while accelerated cell death is evident in acute and chronic degenerative diseases, immunodeficiency and infertility (63). Two main apoptotic signaling pathways have been identified: a death receptor-dependent (extrinsic) pathway and a mitochondrion-dependent (intrinsic) pathway. In the intrinsic apoptotic pathway, the mitochondrion harbors both anti-apoptotic (Bcl-2, Bcl-XL) and pro-apoptotic factors (Smac/Diablo, Apaf-1, cytochrome c, bax, AIF). Cytochrome c, one of these apoptotic factors, is a respiratory chain component that, when expelled to the cytoplasm during the apoptotic chain of events, assembles with two other molecules (Apaf-1 and procaspase 9) to form the apoptosome. This, then, starts apoptosis execution. Some of the stress-inducible players in both pathways include BH3-only molecules (64,65), caspases (66,67) and death receptors (68,69). Because anti-apoptosis molecules (e.g. bcl-2, inhibitors of apoptosis) can be simultaneously down-regulated by genotoxic stress, the ratio of anti- to pro-apoptotic molecules (e.g. bcl-2/bax) can drive a cell into apoptosis. Therefore, similar to the BER pathway, a balance between enzymes within a pathway can determine whether a cell lives or dies. This adaptive imbalance resulting in cell survival might have deleterious effects because this allows for a cell to accumulate genetic mutations and protein damage.


   Antioxidant adaptation
Top
 Abstract
 Introduction
 p53 adaptation
 DNA repair adaptation
 Cell cycle checkpoint adaptation
 Apoptosis adaptation
 Antioxidant adaptation
Carcinogen metabolizing...
 Conclusions and perspectives
 References
 
An adaptive response of antioxidant defences often occurs in cells exposed to oxidative and nitrosative stress. Enzymes critical to this process include catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx). SOD catalyzes the dismutation of superoxide radicals to hydrogen peroxide, which is further metabolized to water and oxygen by catalase and GPx (70) (Figure 1). Another enzyme with antioxidant properties, the mechanisms of which are not entirely understood, is hemeoxygenase-1 (HO-1). Although many studies using animal models of inflammation or examining oxy-radical overload diseases find increased levels of these enzymes (71–88), others find a decrease (89–100). Although these findings are contradicting, consideration should be given to the timing of the assay. Time-course studies can show an early increase in enzymatic activity/levels followed by a decrease (101). More importantly, consistent with the imbalance theme proposed in the above sections, the overall effect of the antioxidant system depends on the intracellular balance between these antioxidant enzymes rather than a single component. For example, increases in SOD in the absence of concomitant catalase and GPx increases would generate an excess amount of hydrogen peroxide and hydroxyl radicals (Figure 1). An imbalance has been shown to occur in tumor cells (102), in tissues undergoing chronic inflammation (91) and in smokers (103–106). Recent studies indicate that p53 may play a role in this process (16).



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  		Fig. 1. Free radical generation and protection from free radicals by SOD, catalase and GPx.

 
One molecule that could be categorized as a Jeckyl and Hyde antioxidant is nitric oxide (NO), first described as endothelium-derived relaxation factor (EDRF) in the 1980 s. NO is a key signaling molecule that mediates many physiological processes, including vasodilation, neurotransmission, host-defence, platelet aggregation and iron metabolism. There is conflicting evidence, however, that this molecule is anti- or pro-carcinogenic. Toward this end, NO has been shown to be an antioxidant (107) with a pro-carcinogenic activity, depending on the genetic background and surrounding tissue milieu (108). Further studies are therefore required to properly assess whether targeting NO for depletion will inhibit or contribute to carcinogenesis. Toward this end, the observation that inhibition of cyclooxygenases (1 and 2) exacerbates colitis and possibly colon cancer associated with this condition offers insight into the contradicting affects of these molecules on carcinogenesis (109–111).


   Carcinogen metabolizing adaptation
Top
 Abstract
 Introduction
 p53 adaptation
 DNA repair adaptation
 Cell cycle checkpoint adaptation
 Apoptosis adaptation
 Antioxidant adaptation
 Carcinogen metabolizing...
Conclusions and perspectives
 References
 
A careful co-ordination and balance of phase I and phase II metabolizing enzymes is necessary for cellular protection against xenobiotics. These enzymes are present in abundance either at the basal level or are induced by genotoxic stress (112–114), and are geared toward changing a bio-active compound into an inactive and excretable compound. Paradoxically, however, most of the intermediates following phase I metabolism are highly reactive with biological molecules, including DNA, RNA and proteins. Therefore, during xenobiotic metabolism, the balance between phase I and phase II enzymes can dramatically alter pharmacokinetics and xenobiotic toxicity. For example, a shift toward increasing phase I enzymatic activity in the absence of phase II changes, either through genetic polymorphisms or genotoxic stress, can exacerbate the impact of carcinogens (114).


   Conclusions and perspectives
Top
 Abstract
 Introduction
 p53 adaptation
 DNA repair adaptation
 Cell cycle checkpoint adaptation
 Apoptosis adaptation
 Antioxidant adaptation
 Carcinogen metabolizing...
 Conclusions and perspectives
References
 
Complex pathways have evolved in mammalian cells aimed at maintaining cellular health. There are many ways to interpret why the expression of specific genes are changed in an environment of genotoxic stress, such as that in chronic inflammation. A very complex profile arises in chronically inflamed tissues, with the induction of pro- and anti-inflammatory cytokines, enzymes such as iNOS and cox-2, and proteins initially believed to protect our genome. Although this protective reaction to the insult sometimes has a beneficial effect, it is becoming increasingly clear that there is a snowball effect with feed-forward pro-mutagenic implications. Guo and Loeb (115) suggested ‘there are many ways that cells can tumble down the path toward genetic instability’. This is important to understand when assessing the use of these molecules in current cancer chemoprevention and treatment strategies. Information supplied by studies on genetic and functional polymorphisms will be beneficial in understanding the genetic components associated with how cells adapt to genotoxic stress.

An additional hypothesis that deserves attention is outlined in Figure 2. An accepted model is that of absolute cellular protection by adaptive increases in genome-protection pathways (Figure 2A). I have argued that this can have pro-carcinogenic consequences (Figure 2B). One model worth exploring, however, is that of intermittent genotoxic stress (Figure 2C). The genome-protection machinery adapts to a genotoxic environment. However, in the absence of this environment, this response is unnecessary, and the ‘protective’ machinery relaxes. Consequently, in a situation of sudden exposure to another or the same genotoxic stress, this machinery is not there. Therefore, there is more risk for genotoxic damage. If this periodic and sudden exposure occurs multiple times, this can have pro-carcinogenic consequences. An analogy of this exposure, with results consistent with this hypothesis, is the epidemiological finding of increased risk of skin cancer with multiple sunburns (116–118). Another example of this would be individuals who quit and re-start smoking multiple times. The hypothesis is that the larger number of times a person quits smoking, the greater the increased lung cancer risk. In support of this hypothesis is the recent finding that cigarette smoke causes an adaptive increase in gene expression patterns, which return to normal when exposure is interrupted (106). However, it does not appear that this type of data has been reported in epidemiological studies, and further examination is necessary to explore such a hypothesis.



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  		Fig. 2. Model depicting how chronic exposure to genotoxic stress (indicated by vertical arrows) leads to an adaptive increase in genome protecting proteins. An accepted understanding has been one of protection by the up-regulation of genome guardians (A). Genome guardian adaptive increases are represented by an increasing size of the cells. It is becoming increasingly clear that these genome guardians paradoxically have pro-mutagenic consequences (B). If this stress is not consistent, with intermittent lapses in genotoxic stress, there will be a down-regulation of these proteins. When the stress appears again, these proteins are not available for protection, possibly leading to a greater amount of cellular damage than with chronic exposure (C).

 

   Acknowledgments
 
Thanks to Dr Frank Berger (University of South Carolina), Dr Miriam Rosin (British Columbia Cancer Agency) and Dr David Christiani (Harvard) for their helpful comments. This work was supported in part by the COBRE funded Center for Colon Cancer Research, NIH Grant# P20 RR17698-01.


   References
Top
 Abstract
 Introduction
 p53 adaptation
 DNA repair adaptation
 Cell cycle checkpoint adaptation
 Apoptosis adaptation
 Antioxidant adaptation
 Carcinogen metabolizing...
 Conclusions and perspectives
 References
 

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Received March 10, 2004; revised April 22, 2004; accepted May 18, 2004.


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