Tumor Hypoxia as a Modifier of DNA Strand Break and Cross-Link Repair

Chan, Norman; Koch, Cameron J.; Bristow, Robert G.

doi:10.2174/156652409788167050

Cited by 34 publications

(28 citation statements)

References 88 publications

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“…4 and Supplementary Figs. S4 and S5) as previously reported (51,52). In that context, we observed that knocking down Nupr1 expression increases cell death, induces DNA damage, and alters the expression of several genes involved in DNA repair, some of them being regulated by hypoxia and by glucose starvation.…”

Section: Discussionsupporting

confidence: 81%

Nupr1-Aurora Kinase A Pathway Provides Protection against Metabolic Stress-Mediated Autophagic-Associated Cell Death

Hamidi

Cano

Grasso

et al. 2012

Clinical Cancer Research

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Purpose: The limited supply of oxygen and nutrients is thought to result in rigorous selection of cells that will eventually form the tumor.Experimental Design: Nupr1 expression pattern was analyzed in human tissue microarray (TMA) and correlated with survival time of the patient. Microarray analysis was conducted on MiaPaCa2 cells subjected to metabolic stress in Nupr1-silenced conditions. DNA repair and cell cycle-associated gene expression was confirmed by real-time quantitative PCR (qRT-PCR). Nupr1 and AURKA protective role were analyzed using RNA interference (RNAi) silencing or overexpression. DNA damage and autophagy were analyzed by Western blot analysis and immunofluorescence.Results: We showed that both Nupr1 and HIF1a are coexpressed in human pancreatic ductal adenocarcinoma (PDAC) samples and negatively correlate with survival time. PDAC-derived cells submitted to hypoxia and/or glucose starvation induce DNA damage-dependent cell death concomitantly to the overexpression of stress protein Nupr1. Affymetrix-based transcriptoma analysis reveals that Nupr1 knockdown enhances DNA damage and alters the expression of several genes involved in DNA repair and cell-cycle progression. Expression of some of these genes is common to hypoxia and glucose starvation, such as Aurka gene, suggesting that Nupr1 overexpression counteracts the transcriptional changes occurring under metabolic stress. The molecular mechanism by which hypoxia and glucose starvation induce cell death involves autophagy-associated, but not caspase-dependent, cell death. Finally, we have found that AURKA expression is partially regulated by Nupr1 and plays a major role in this response.Conclusions: Our data reveal that Nupr1 is involved in a defense mechanism that promotes pancreatic cancer cell survival when exposed to metabolic stress.

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Section: Discussionsupporting

confidence: 81%

Nupr1-Aurora Kinase A Pathway Provides Protection against Metabolic Stress-Mediated Autophagic-Associated Cell Death

Hamidi

Cano

Grasso

et al. 2012

Clinical Cancer Research

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“…18 F-FMISO, 18 F-FAZA, 18 F-EF5, and 60 Cu-ATSM), or single photon emission computed tomography (SPECT;…”

Section: Discussionmentioning

confidence: 99%

“…18). The relative level of oxygen at the time of irradiation determines the efficacy of radiotherapy, by limiting the type and number of lethal DNA lesions (e.g., DNA DSBs).…”

Section: Models Of Hypoxia and Resistance To Radiotherapy And Chemothmentioning

confidence: 99%

“Contextual” Synthetic Lethality and/or Loss of Heterozygosity: Tumor Hypoxia and Modification of DNA Repair

Chan

Bristow

2010

Clinical Cancer Research

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102

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Hypoxia exists in every solid tumor and is associated with poor prognosis because of both local and systemic therapeutic resistance. Recent studies have focused on the interaction between tumor cell genetics and the dynamic state of oxygenation and metabolism. Hypoxia generates aggressive tumor cell phenotypes in part owing to ongoing genetic instability and a "mutator" phenotype. The latter may be due to suppression of DNA mismatch repair (MMR), nucleotide excision repair (NER), and double-strand break (DSB) repair. We propose a theoretical model in which hypoxia-mediated defects in DNA repair can lead to "contextual loss of heterozygosity" and drive oncogenesis. Additionally, hypoxia-mediated repair defects can be specifically targeted by DNA damaging agents and/or "contextual synthetic lethality" to kill repair-deficient cells and preserve the therapeutic ratio. These proposed concepts support the interrogation of solid tumors to document repair defects in both oxic and hypoxic tumor subregions as a conduit to novel clinical trials within the context of personalized medicine. Clin Cancer Res; 16(18); 4553-60. ©2010 AACR.The microenvironment of solid tumors differs greatly from that of normal tissues as it can contain regions of hypoxia (a decreased level of oxygen), increased interstitial fluid pressure, and decreased pH and nutrient delivery (1, 2). Hypoxia is associated with both local and systemic therapy resistance, and decreased disease-free survival has been observed in many human cancers (3-11). Importantly, hypoxia is an adverse prognostic factor in cancers treated with either radiotherapy or surgery. Hence hypoxia is not only a determinant of local radio-or chemoresistance, but also tumor progression and systemic metastasis. The latter may be due to altered transcription and translation of metastatic genes, but could also be secondary to clonal selection of a "mutator" phenotype (12,13). This unstable phenotype may result from hypoxia-mediated suppression of DNA mismatch repair (MMR), nucleotide excision repair (NER), and doublestrand break (DSB) repair [whether by homologous recombination (HR) or nonhomologous end-joining (NHEJ)]. Suppression of DNA repair in oxic and hypoxic cells may, therefore, have profound consequences, given that residual or misrepaired DNA breaks can be highly carcinogenic and generate chromosomal alterations in oncogenes and tumor suppressor genes during tumor progression (14,15).This report critically reviews preclinical and clinical studies that link tumor hypoxia and DNA repair pathways as drivers of genetic instability and tumor progression. We also highlight recent work in which these DNA repair defects in aggressive cancer cells can be exploited with novel therapeutic approaches. Models of Hypoxia and Resistance to Radiotherapy and ChemotherapyThe abnormal vasculature of tumors resulting from unregulated angiogenesis is probably the most important contributor to the development of both chronic and acute hypoxia in the majority of solid tumors (reviewed in ref. ...

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“…Koshiji et al demonstrated that Hif-1/HIF-1 (PASD8) inhibits the DNA mismatch repair system (MSH2 and MSH6), which is responsible for genetic instability [8]. Other researchers have also reported that hypoxia down regulates the expression of DNA double-stranded break repair genes [9,10] [11,12]. These data support the concept that defective DNA repair pathways cause genomic instability within the tumor microenvironment.…”

mentioning

confidence: 81%

Update meta-analysis on 1790G/A polymorphism and cancer risk: Evidence from 26 studies

Liu¹,

Shi²,

Yang³

et al. 2014

neo

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The results from the published studies on the association between hypoxia-inducible factor-1(Hif-1/HIF-1) polymorphisms and cancer risk are conflicting. The common 1790G/A rs11549467) genetic polymorphism has been reported to be functional and may contribute to genetic susceptibility to cancers. However, the association between 1790G/A (rs11549467) and cancer risk remains inconclusive.To better understand the role of 1790G/A (rs11549467) polymorphism in cancer, we conducted this comprehensive metaanalysis encompassing 6337 cases and 9302 controls.Overall, the 1790G/A (rs11549467) genetic polymorphism was associated with higher cancer risk. In the stratified analysis, significant associations were found between the Hif-1/HIF-1 1790G/A polymorphism and lung cancer, pancreatic cancer and oral squamous cell carcinoma. We also observed that the AA genotype might modulate lung cancer (OR=5. (AA vs. GG) and recessive genetic model (AA vs. AG/GG) among Caucasian population. When stratified by study design, significantly elevated susceptibility to cancer was found among hospital-based studies.These findings suggested that the 1790G/A (rs11549467) genetic polymorphism may contribute to the susceptibility of cancers except gynecologic cancer, especially in homozygote comparison and recessive genetic model among Caucasian population, and this SNP was significantly associated with the lung cancer, pancreatic cancer and oral squamous cell carcinoma (OSCC). The phenomenon also indicates that the SNP functions as a recessive mutation needs to be verified or linked with functional studies.

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Tumor Hypoxia as a Modifier of DNA Strand Break and Cross-Link Repair

Cited by 34 publications

References 88 publications

Nupr1-Aurora Kinase A Pathway Provides Protection against Metabolic Stress-Mediated Autophagic-Associated Cell Death

Nupr1-Aurora Kinase A Pathway Provides Protection against Metabolic Stress-Mediated Autophagic-Associated Cell Death

“Contextual” Synthetic Lethality and/or Loss of Heterozygosity: Tumor Hypoxia and Modification of DNA Repair

Update meta-analysis on 1790G/A polymorphism and cancer risk: Evidence from 26 studies

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