Mismatch Repair Protein Deficiency Compromises Cisplatin-induced Apoptotic Signaling

Topping, Ryan P.; Wilkinson, John; Scarpinato, Karin

doi:10.1074/jbc.m809303200

Cited by 66 publications

(49 citation statements)

References 33 publications

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“…Silencing of RECQL1 induces mitotic catastrophe (5), and CDDP is involved in apoptosis, mitotic catastrophe, and necrosis (29)(30)(31)(32). The data in this study were mostly consistent with these reports, as described in the following text.…”

Section: Discussionsupporting

confidence: 82%

RECQL1 and WRN Proteins Are Potential Therapeutic Targets in Head and Neck Squamous Cell Carcinoma

Arai

Chano²,

Futami³

et al. 2011

Cancer Research

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RECQL1 and WRN proteins are RecQ DNA helicases that participate in suppression of DNA hyperrecombination and repair. In this study, we report evidence supporting their candidacy as cancer therapeutic targets. In hypopharyngeal carcinomas, which have the worst prognosis among head and neck squamous cell carcinomas (HNSCC) that are rapidly rising in incidence, we found that RECQL1 and WRN proteins are highly expressed and that siRNA-mediated silencing of either gene suppressed carcinoma cell growth in vitro. Similarly, siRNA administration in a murine xenograft model of hypopharyngeal carcinoma markedly inhibited tumor growth. Moreover, combining either siRNA with cis-platinum (II) diammine dichloride significantly augmented the in vivo anticancer effects of this drug that is used commonly in HNSCC treatment. Notably, we observed no recurrence of some tumors following siRNA treatment in this model. Our findings offer a preclinical proof of concept for RECQL1 and WRN proteins as novel therapeutic targets to treat aggressive HNSCC and perhaps other cancers. Cancer Res; 71(13); 4598-607. Ó2011 AACR.

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Section: Discussionsupporting

confidence: 82%

RECQL1 and WRN Proteins Are Potential Therapeutic Targets in Head and Neck Squamous Cell Carcinoma

Arai

Chano²,

Futami³

et al. 2011

Cancer Research

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“…2 and 5). Thus, although both p53-dependent and -independent mechanisms may underlie the apoptotic resistance of MMRdeficient cells (20,45,46), in our study the effect appears largely p53-dependent.…”

Section: Discussionmentioning

confidence: 67%

hMSH2 Recruits ATR to DNA Damage Sites for Activation during DNA Damage-induced Apoptosis

Pabla

McIlhatton

et al. 2011

Journal of Biological Chemistry

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DNA damage response (DDR) activates a complex signaling network that triggers DNA repair, cell cycle arrest, and/or cell death. Depending on the type and severity of DNA lesion, DDR is controlled by "master" regulators including ATM and ATR protein kinases. Cisplatin, a major chemotherapy drug that cross-links DNA, induces ATR-dependent DDR, resulting in apoptosis. However, it is unclear how ATR is activated. To identify the key regulators of ATR, we analyzed the proteins that associate with ATR after cisplatin treatment by blue native-PAGE and co-immunoprecipitation. The mismatch repair protein hMSH2 was found to be a major ATR-binding protein.Functionally, ATR activation and its recruitment to nuclear foci during cisplatin treatment were attenuated, and DNA damage signaling, involving Chk2, p53, and PUMA-␣, was suppressed in hMSH2-deficient cells. ATR activation induced by the DNA methylating agent N-methyl-N-nitrosourea was also shown to be hMSH2-dependent. Intriguingly, hMSH2-mediated ATR recruitment and activation appeared independent of replication protein A, Rad17, and the Rad9-Hus1-Rad1 protein complex. Together the results support a hMSH2-dependent pathway of ATR activation and downstream Chk2/p53 signaling. DNA damage response (DDR)3 is essential for the maintenance of the integrity of the genome (1-5). As a complex multistep process, DDR involves the recognition of DNA damage, activation of DNA damage-responsive protein kinases, signal amplification by downstream protein kinases, and activation of the effector proteins that trigger various cellular processes. At low levels of DNA damage, activation of DDR results in cell cycle arrest and DNA repair. However, at higher doses, DDR signaling frequently results in cell death by apoptosis (1-5). The phosphoinositide 3-kinase-related protein kinases, ATM (ataxiatelangiectasia mutated) and ATR (ATM-and Rad3-related), are the key regulators of DDR (1-8). Once activated, ATM and ATR regulate an array of substrates including Chk1 and Chk2, which culminate in DNA repair, cell cycle arrest, and/or apoptosis. Although ATM is generally activated by doublestranded DNA breaks, ATR activation can result from different types of DNA lesion including single-stranded breaks, replication stress, base adducts, and DNA cross-links (8, 9). In the canonical model, ATR activation involves the recruitment of the ATR-ATRIP (ATR-interacting protein) and the Rad9-Hus1-Rad1 (9-1-1) protein complexes to the DNA damage site via replication protein A (RPA). As a result, the 9-1-1 complex brings topoisomerase-binding protein-1 (TopBP1, an ATR activator) close to ATR for ATR activation (1,5,8). However, alternative pathways of ATR activation may exist. For example, mismatch repair (MMR) proteins have been implicated in ATR activation under certain experimental conditions (10 -12).The MMR system is important for DNA replication and repair (13-18). In mammalian cells, MMR is composed of five MutS homologues (MSH) and four MutL homologue proteins. The function of MMR is to first recognize D...

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“…A number of clinical studies have demonstrated that MMR deficiency is associated with lack of benefit from 5-fluorouracil-based chemotherapy at the expense of toxicity and even increased mortality; however, the results are heterogeneous [29,30,[33][34][35][36]. With regard to platinum-based agents, in vitro analysis of MMR-deficient cell lines suggest that, to a lesser degree, MMRdeficient cells may be more tolerant to purine cross-linking damage induced by cisplatin [37,38].…”

Section: Microsatellite Instabilitymentioning

confidence: 96%

Application of molecular techniques in the diagnosis, prognosis and management of patients with colorectal cancer: a practical approach

2012

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Mismatch Repair Protein Deficiency Compromises Cisplatin-induced Apoptotic Signaling

Cited by 66 publications

References 33 publications

RECQL1 and WRN Proteins Are Potential Therapeutic Targets in Head and Neck Squamous Cell Carcinoma

RECQL1 and WRN Proteins Are Potential Therapeutic Targets in Head and Neck Squamous Cell Carcinoma

hMSH2 Recruits ATR to DNA Damage Sites for Activation during DNA Damage-induced Apoptosis

Application of molecular techniques in the diagnosis, prognosis and management of patients with colorectal cancer: a practical approach

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