Chk2 Protects against Radiation-Induced Genomic Instability

MacLaren, Ann; Slavin, Daniela A; McGowan, Clare H.

doi:10.1667/rr1603.1

Cited by 4 publications

(4 citation statements)

References 64 publications

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“…For instance, dysfunctionality of ATM in B-cell chronic lymphocytic leukemia, which predominantly harbors wild-type p53, correlates with resistance to fludarabine and poor prognosis in patients (38–40). Similarly, 83% of tumor specimens from patients with NSCLC, a highly refractory cancer with a poor survival rate, and 23% of clinical ovarian cancers are reported to be Chk2-defective (41–44). Although not investigated in these reports, it is tempting to speculate, based on our studies, that loss of Ser20 phosphorylation may have induced refractoriness in these cancers.…”

Section: Discussionmentioning

confidence: 99%

Functional Activation of Mutant p53 by Platinum Analogues in Cisplatin-Resistant Cells Is Dependent on Phosphorylation

Xie

Siddik

2017

Molecular Cancer Research

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Dysfunctionality of the p53 tumor suppressor is a major cause of therapeutic drug resistance in cancer. Recently we reported that mutant, but otherwise functional, p53V172F was inactivated in cisplatin-resistant 2780CP/Cl-16 and 2780CP/Cl-24 human ovarian tumor cells by increased recruitment of the inhibitor MDM4. The current study demonstrates that, unlike cisplatin, platinum analogs oxaliplatin and DACH-diacetato-dichloro-Pt(IV) (DAP), strongly stabilize and activate p53V172F in resistant cells, as indicated by prolonged p53 half-life and transactivation of targets p21 (CDKN1A) and MDM2. This increase in MDM2 reduced MDM4 levels in cell lysates as well as the p53 immunocomplex and prevented reversion of p53 to the inactive p53-MDM2-MDM4 bound state. Phosphorylation of p53 at Ser15 was demonstrated by all three drugs in sensitive A2780 and corresponding resistant 2780CP/Cl-16 and 2780CP/Cl-24 cell lines. However, cisplatin induced Ser20 phosphorylation in A2780 cells only, but not in resistant cells; in contrast, both DAP and oxaliplatin induced this phosphorylation in all three cell lines. The inference that Ser20 phosphorylation is more important for p53 activation was confirmed by ectopic expression of a phosphomimetic (S20D) mutant p53 that displayed reduced binding, relative to wild-type p53, to both MDM2 and MDM4 in p53-knockout A2780 cells. In consonance, temporal studies demonstrated drug-induced Ser15 phosphorylation coincided with p53 stabilization, whereas Ser20 phosphorylation coincided with p53 transactivation. Implications Cisplatin fails to activate the pathway involved in phosphorylating mutant p53V172F at Ser20 in resistant cells, but this phosphorylation is restored by oxaliplatin and DAP that reactivates p53 function and circumvents cisplatin resistance.

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Section: Discussionmentioning

confidence: 99%

Functional Activation of Mutant p53 by Platinum Analogues in Cisplatin-Resistant Cells Is Dependent on Phosphorylation

Xie

Siddik

2017

Molecular Cancer Research

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“…The importance of Chk2 in DNA damage response can be readily appreciated from reports that Chk2-null cells from genetically engineered mice are remarkably resistant to some DNA damaging agents [181,187,188]. The significance of these observations becomes clear when it is noted that Chk2 downregulation has been correlated with resistance to cisplatin in lung cancer cell lines [189].…”

Section: Mechanisms Of Resistance Involving P53mentioning

confidence: 99%

Resistance and gain-of-resistance phenotypes in cancers harboring wild-type p53

Martinez-Rivera

Siddik

2012

Biochemical Pharmacology

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Chemotherapy is the bedrock for the clinical management of cancer, and the tumor suppressor p53 has a central role in this therapeutic modality. This protein facilitates favorable antitumor drug response through a variety of key cellular functions, including cell cycle arrest, senescence, and apoptosis. These functions essentially cease once p53 becomes mutated, as occurs in ~50% of cancers, and some p53 mutants even exhibit gain-of-function effects, which lead to greater drug resistance. However, it is becoming increasingly evident that resistance is also seen in cancers harboring wild-type p53. In this review, we discuss how wild-type p53 is inactivated to render cells resistant to antitumor drugs. This may occur through various mechanisms, including an increase in proteasomal degradation, defects in post-translational modification, and downstream defects in p53 target genes. We also consider evidence that the resistance seen in wild-type p53 cancers can be substantially greater than that seen in mutant p53 cancers, and this poses a far greater challenge for efforts to design strategies that increase drug response in resistant cancers already primed with wild-type p53. Because the mechanisms contributing to this wild-type p53 “gain-of-resistance” phenotype are largely unknown, a concerted research effort is needed to identify the underlying basis for the occurrence of this phenotype and, in parallel, to explore the possibility that the phenotype may be a product of wild-type p53 gain-of-function effects. Such studies are essential to lay the foundation for a rational therapeutic approach in the treatment of resistant wild-type p53 cancers.

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“…In p53-defective cells, heat shock factor 1-mediated aneuploidy was more common (10). With the disruption of both Chk2 and p53 function after irradiationinduced DNA damage, a synergistic increase in genomic instability was seen in an in vitro study (11). In p53 ser 23 mutant mice, lymphoma and sarcoma developed, whereas alternatively, in a p53-stabilized status, proper apoptosis function was maintained and mice were protected from tumorigenesis (12).…”

Section: Introductionmentioning

confidence: 99%