ATM as a target for novel radiosensitizers

Sarkaria, Jann N.; Eshleman, Jeffrey S.

doi:10.1053/srao.2001.26030

Cited by 55 publications

(39 citation statements)

References 82 publications

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“…37,38 The role of p53 in apoptosis induced by a variety of stress stimuli was thought, initially, to center on its role as a transcription factor modulating gene expression. In cells with functional p53 protein, a post-translational increase in levels of p53 39,40 occurs in response to irradiation, which appears to be mediated through the ATM proteins, 41,42 and, ultimately, results in an increase in the level of the cyclin-dependent kinase inhibitory protein, p21 Waf1=cip1 , and the proapoptotic protein, Bax. 39,43,44 Recent work has also provided evidence that p53 can contribute to the induction of apoptosis via non-nuclear pathways through the initiation of proapoptotic mechanisms that involve the physical interaction of the core DNAbinding domain of p53 with apoptosis regulators, such as Bcl-2 and Bcl-X L , at the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

HDAC Inhibitor, Valproic Acid, Induces p53-Dependent Radiosensitization of Colon Cancer Cells

Chen

Wong

Radany

et al. 2009

Cancer Biotherapy and Radiopharmaceuticals

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Agents that inhibit histone deacetylases (HDAC inhibitors) have been shown to enhance radiation response. The aim of this study was to evaluate the effects of low, minimally cytotoxic concentrations of the HDAC inhibitor, valproic acid (VPA), on radiation response of colorectal cancer cells. Cell lines LS174T and an isogenic pair of HCT116, which differed only for the presence of wild-type p53, were exposed to ionizing radiation (IR) alone, VPA alone, or the combination. Clonogenic survival, g-H2AX induction, apoptosis, changes in mitochondrial membrane potential, and mitochondrial levels of p53 and Bcl-2 family proteins were assessed. In vivo studies monitored tumor growth suppression after therapy in mice bearing HCT116=p53 þ=þ and HCT116=p53 À=À tumor xenografts. VPA led to radiosensitization, which was dependent on p53 status. A decrease in clonogenic survival, an increase in apoptosis, and an increase in levels of g-H2AX were observed after VPAþIR, compared to IR alone, in wild-type p53 cells (LS174T and HCT116=p53 þ=þ ), as opposed to p53 null cells (HCT116=p53 À=À). Exposure to VPA resulted in enhancement of IR-induced mitochondrial localizations of Bax and Bcl-xL, mitochondrial membrane potential, and cytochrome c release only in wild-type p53 cell lines. VPA also enhanced tumor growth suppression after IR only in wild-type p53 xenografts. These data suggest that VPA may have an important role in enhancing radiotherapy response in colorectal cancer, particularly in tumors with the wildtype p53 genotype.

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Section: Discussionmentioning

confidence: 99%

HDAC Inhibitor, Valproic Acid, Induces p53-Dependent Radiosensitization of Colon Cancer Cells

Chen

Wong

Radany

et al. 2009

Cancer Biotherapy and Radiopharmaceuticals

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“…Following the exposure to genotoxic agents, the serine/threonine kinase ATM directly and indirectly phosphorylates several substrates in order to orchestrate the cellular DNA-damage response (DDR), activating a signaling cascade which induces DNA repair, cell-cycle checkpoint activation and, eventually, apoptosis or senescence (Lavin, 2008). Interestingly, ATM-deficient cells display an increased sensitivity to genotoxic agents (Meyn et al, 1994;Savitsky et al, 1995;Ku¨hne et al, 2004), and chemical inhibition of ATM induces cellular chemo-and radio-resistance (Sarkaria et al, 1998(Sarkaria et al, , 1999Sarkaria and Eshleman 2001).…”

Section: Introductionmentioning

confidence: 99%

HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

et al. 2011

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DNA-damaging therapies represent a keystone in cancer treatment. Unfortunately, many tumors often relapse because of a group of cancer cells, which are resistant to conventional therapies. High-mobility group A (HMGA) proteins has a key role in cell transformation, and their overexpression is a common feature of human malignant neoplasias, representing a poor prognostic index often correlated to anti-cancer drug resistance. Our previous results demonstrated that HMGA1 is a substrate of ataxiatelangiectasia mutated (ATM), the main cellular sensor of genotoxic stress. Here we also report thatHMGA2, the other member of the HMGA family, is a novel substrate of ATM. Interestingly, we found that HMGA proteins positively regulate ATM gene expression. Moreover, induction of ATM kinase activity by DNA-damaging agents enhances HMGA-dependent transcriptional activation of ATM promoter, suggesting that ATM expression is modulated by a DNA-damage-and HMGA-dependent positive feedback loop. Finally, inhibition of HMGA expression in mouse embryonic fibroblasts and in cancer cells strongly reduces ATM protein levels, impairing the cellular DNA-damage response and enhancing the sensitivity to DNA-damaging agents. These findings indicate this novel HMGA-ATM pathway as a new potential target to improve the effectiveness of conventional anti-neoplastic treatments on the genotoxic-drug resistant cancer cells.

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“…ATM, or ataxia-telangiectasia mutated was first identified in AT patients in 1995 (Savitsky et al, 1995). ATM plays critical roles in radiationinduced responses (Kastan et al, 2001;Kurz and Lees-Miller, 2004), and has been identified as a potential target for novel radiosensitizers (Sarkaria andEshleman, 2001, Ahmed andLi 2007). For example, small molecule inhibitors of ATM or downstream signaling molecules (Kim et al, 1999;Jung and Dritschilo, 2001) may offer a strategy to sensitize tumors to the lethal effects of ionizing radiation while sparing normal tissues.…”

Section: Introductionmentioning

confidence: 99%

Integrated Bioinformatics for Radiation-Induced Pathway Analysis from Proteomics and Microarray Data

Hu¹,

Huang²,

Cheema³

et al. 2008

J Proteomics Bioinform

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Functional analysis and interpretation of large-scale proteomics and gene expression data require effective use of bioinformatics tools and public knowledge resources coupled with expert-guided examination. An integrated bioinformatics approach was used to analyze cellular pathways in response to ionizing radiation. ATM, or ataxia-telangiectasia mutated , a serine-threonine protein kinase, plays critical roles in radiation responses, including cell cycle arrest and DNA repair. We analyzed radiation responsive pathways based on 2D-gel/MS proteomics and microarray gene expression data from fibroblasts expressing wild type or mutant ATM gene. The analysis showed that metabolism was significantly affected by radiation in an ATM dependent manner. In particular, purine metabolic pathways were differentially changed in the two cell lines. The expression of ribonucleoside-diphosphate reductase subunit M2 (RRM2) was increased in ATM-wild type cells at both mRNA and protein levels, but no changes were detected in ATM-mutated cells. Increased expression of p53 was observed 30min after irradiation of the ATM-wild type cells. These results suggest that RRM2 is a downstream target of the ATM-p53 pathway that mediates radiation-induced DNA repair. We demonstrated that the integrated bioinformatics approach facilitated pathway analysis, hypothesis generation and target gene/protein identification.

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ATM as a target for novel radiosensitizers

Cited by 55 publications

References 82 publications

HDAC Inhibitor, Valproic Acid, Induces p53-Dependent Radiosensitization of Colon Cancer Cells

HDAC Inhibitor, Valproic Acid, Induces p53-Dependent Radiosensitization of Colon Cancer Cells

HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

Integrated Bioinformatics for Radiation-Induced Pathway Analysis from Proteomics and Microarray Data

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