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Search Results: 1 - 10 of 53007 matches for " David Sidransky "
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Targeting of mutant hogg1 in mammalian mitochondria and nucleus: effect on cellular survival upon oxidative stress
Aditi Chatterjee, Elizabeth Mambo, Yonggang Zhang, Theodore DeWeese, David Sidransky
BMC Cancer , 2006, DOI: 10.1186/1471-2407-6-235
Abstract: We over-expressed wild type and R229Q mutant hOGG1 in the nucleus and mitochondria of cells lacking mitochondrial hOGG1 expression through an expression vector containing nuclear and mitochondrial targeting sequence respectively. We used quantitative real time PCR to analyze mtDNA integrity after exposure to oxidative damaging agents, in cells transfected with or without mitochondrially-targeted mutant hogg1.Over-expression of wild type hOgg1 in both nucleus and mitochondria resulted in increased cellular survival when compared to vector or mutant over-expression of hOGG1. Interestingly, mitochondrially-targeted mutant hogg1 resulted in more cell death than nuclear targeted mutant hogg1 upon exposure of cells to oxidative damage. Additional we examined mitochondrial DNA integrity after oxidative damage exposure using real-time quantitative PCR. The presence of mutant hogg1 in the mitochondria resulted in reduced mitochondrial DNA integrity when compared to the wild type. Our work indicates that the R229Q hOGG1 mutation failed to protect cells from oxidative damage and that such mutations in cancer may be more detrimental to cellular survival when present in the mitochondria than in the nucleus.These findings suggest that deficiencies in hOGG1, especially in the mitochondria may lead to reduced mitochondrial DNA integrity, consequently resulting in decreased cell viability.The detection of mitochondrial DNA (mtDNA) mutations in several human diseases has stimulated interest in understanding how the integrity of the mitochondrial genome is maintained [1-4]. It is believed that these mutations likely result from the exposure of mtDNA to reactive oxygen species (ROS). mtDNA is continuously exposed to ROS which are formed as byproducts of normal cell metabolism and during exposure to physical and chemical agents such as γ-irradiation, UV-irradiation or H2O2. Lack of protective histones, proximity to oxidative phosphorylation and limited capacity for repair of DNA damage
Following Mitochondrial Footprints through a Long Mucosal Path to Lung Cancer
Santanu Dasgupta, Rex C. Yung, William H. Westra, David A. Rini, Johann Brandes, David Sidransky
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006533
Abstract: Background Mitochondrial DNA (mtDNA) mutations are reported in different tumors. However, there is no information on the temporal development of the mtDNA mutations/content alteration and their extent in normal and abnormal mucosa continuously exposed to tobacco smoke in lung cancer patients. Methodology We examined the pattern of mtDNA alteration (mtDNA mutation and content index) in 25 airway mucosal biopsies, corresponding tumors and normal lymph nodes obtained from three patients with primary lung cancers. In addition, we examined the pattern of mtDNA mutation in corresponding tumors and normal lymph nodes obtained from eight other patients with primary lung cancers. The entire 16.5 kb mitochondrial genome was sequenced on Affymetrix Mitochip v2.0 sequencing platform in every sample. To examine mtDNA content index, we performed real-time PCR analysis. Principal Findings The airway mucosal biopsies obtained from three lung cancer patients were histopathologically negative but exhibited multiple clonal mtDNA mutations detectable in the corresponding tumors. One of the patients was operated twice for the removal of tumor from the right upper and left lower lobe respectively within a span of two years. Both of these tumors exhibited twenty identical mtDNA mutations. MtDNA content increased significantly (P<0.001) in the lung cancer and all the histologically negative mucosal biopsies except one compared to the control lymph node. Conclusions/Significance: Our results document the extent of massive clonal patches that develop in lifetime smokers and ultimately give rise to clinically significant cancers. These observations shed light on the extent of disease in the airway of smokers traceable through mtDNA mutation. MtDNA mutation could be a reliable tool for molecular assessment of respiratory epithelium exposed to continuous smoke as well as disease detection and monitoring. Functional analysis of the pathogenic mtDNA mutations may be useful to understand their role in lung tumorigenesis.
Adenylate Kinase 3 Sensitizes Cells to Cigarette Smoke Condensate Vapor Induced Cisplatin Resistance
Xiaofei Chang,Rajani Ravi,Vui Pham,Atul Bedi,Aditi Chatterjee,David Sidransky
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020806
Abstract: The major established etiologic risk factor for bladder cancer is cigarette smoking and one of the major antineoplastic agents used for the treatment of advanced bladder cancer is cisplatin. A number of reports have suggested that cancer patients who smoke while receiving treatment have lower rates of response and decreased efficacy of cancer therapies.
Dose-Dependent Activation of Putative Oncogene SBSN by BORIS
Daria Gaykalova, Rajita Vatapalli, Chad A. Glazer, Sheetal Bhan, Chunbo Shao, David Sidransky, Patrick K. Ha, Joseph A. Califano
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040389
Abstract: Testis-specific transcription factor BORIS (Brother of the Regulator of Imprinted Sites), a paralog and proposed functional antagonist of the widely expressed CTCF, is abnormally expressed in multiple tumor types and has been implicated in the epigenetic activation of cancer-testis antigens (CTAs). We have reported previously that suprabasin (SBSN), whose expression is restricted to the epidermis, is epigenetically derepressed in lung cancer. In this work, we establish that SBSN is a novel non-CTA target of BORIS epigenetic regulation. With the use of a doxycycline-inducible BORIS expressing vector, we demonstrate that relative BORIS dosage is critical for SBSN activation. At lower concentrations, BORIS induces demethylation of the SBSN CpG island and disruption and activation of chromatin around the SBSN transcription start site (TSS), resulting in a 35-fold increase in SBSN expression in the H358 human lung cancer cell line. Interestingly, increasing BORIS concentrations leads to a subsequent reduction in SBSN expression via chromatin repression. In a similar manner, increase in BORIS concentrations leads to eventual decrease of cell growth and colony formation. This is the first report demonstrating that different amount of BORIS defines its varied effects on the expression of a target gene via chromatin structure reorganization.
Multiple strand displacement amplification of mitochondrial DNA from clinical samples
Samantha Maragh, John P Jakupciak, Paul D Wagner, William N Rom, David Sidransky, Sudhir Srivastava, Catherine D O'Connell
BMC Medical Genetics , 2008, DOI: 10.1186/1471-2350-9-7
Abstract: DNA was isolated from clinical samples and sent to NIST. Samples were amplified by PCR and those with no visible amplification were re-amplified using the Multiple Displacement Amplificaiton technique of whole genome amplification. All samples were analyzed by mitochip for mitochondrial DNA sequence to compare sequence concordance of the WGA samples with respect to native DNA. Real-Time PCR analysis was conducted to determine the level of WGA amplification for both nuclear and mtDNA.In total, 19 samples were compared and the concordance rate between WGA and native mtDNA sequences was 99.995%. All of the cancer associated mutations in the native mtDNA were detected in the WGA amplified material and heteroplasmies in the native mtDNA were detected with high fidelity in the WGA material. In addition to the native mtDNA sequence present in the sample, 13 new heteroplasmies were detected in the WGA material.Genetic screening of mtDNA amplified by WGA is applicable for the detection of cancer associated mutations. Our results show the feasibility of this method for: 1) increasing the amount of DNA available for analysis, 2) recovering the identical mtDNA sequence, 3) accurately detecting mtDNA point mutations associated with cancer.It is often the case that an insufficient quantity of DNA can be isolated from clinical specimens and controls for full genome analysis. The quantity of DNA is particularly limited in patient tumor specimens, most notably in early tumors with limited mass and therefore, insufficient DNA may be available to perform the multiple analyses required for full genome screening [1-4]. Whole genome amplification (WGA) methods have been developed to solve the problem of insufficient quantities of DNA [5,6]. Using these technologies, investigators have been successful in applying genome scanning technologies to patient cohort samples collected years ago that are not recoverable by other means [7]. WGA is useful for amplification of DNA from stored histolo
Somatic mutation and gain of copy number of PIK3CA in human breast cancer
Guojun Wu, Mingzhao Xing, Elizabeth Mambo, Xin Huang, Junwei Liu, Zhongmin Guo, Aditi Chatterjee, David Goldenberg, Susanne M Gollin, Saraswati Sukumar, Barry Trink, David Sidransky
Breast Cancer Research , 2005, DOI: 10.1186/bcr1262
Abstract: Fifteen breast cancer cell lines and 92 primary breast tumors (33 with matched normal tissue) were used to check somatic mutation and gene copy number of PIK3CA. For the somatic mutation study, we specifically checked exons 1, 9, and 20, which have been reported to be hot spots in colon cancer. For the analysis of the gene copy number, we used quantitative real-time PCR and fluorescence in situ hybridization. We also treated several breast cancer cells with the PIK3CA inhibitor LY294002 and compared the apoptosis status in cells with and without PIK3CA mutation.We identified a 20.6% (19 of 92) and 33.3% (5 of 15) PIK3CA somatic mutation frequency in primary breast tumors and cell lines, respectively. We also found that 8.7% (8 of 92) of the tumors harbored a gain of PIK3CA gene copy number. Only four cases in this study contained both an increase in the gene copy number and a somatic mutation. In addition, mutation of PIK3CA correlated with the status of Akt phosphorylation in some breast cancer cells and inhibition of PIK3CA-induced increased apoptosis in breast cancer cells with PIK3CA mutation.Somatic mutation rather than a gain of gene copy number of PIK3CA is the frequent genetic alteration that contributes to human breast cancer progression. The frequent and clustered mutations within PIK3CA make it an attractive molecular marker for early detection and a promising therapeutic target in breast cancer.Phosphatidylinositol 3-kinases (PI3Ks) are a group of lipid kinases composed of 85-kDa and 110-kDa subunits. The 85-kDa subunit lacks PI3K activity and acts as adaptor, coupling the 110-kDa subunit (P110) to activated protein tyrosine kinases and generating second messengers by phosphorylating membrane inositol lipids at the D3 position. The resulting phosphatidylinositol derivatives then permit activation of downstream effectors that are involved in cell proliferation, survival, metabolism, cytoskeletal reorganization, and membrane trafficking [1,2].PIK3CA, the g
Neurofilament Heavy Polypeptide Regulates the Akt-β-Catenin Pathway in Human Esophageal Squamous Cell Carcinoma
Myoung Sook Kim,Xiaofei Chang,Cynthia LeBron,Jatin K. Nagpal,Juna Lee,Yiping Huang,Keishi Yamashita,Barry Trink,Edward A. Ratovitski,David Sidransky
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009003
Abstract: Aerobic glycolysis and mitochondrial dysfunction are common features of aggressive cancer growth. We observed promoter methylation and loss of expression in neurofilament heavy polypeptide (NEFH) in a significant proportion of primary esophageal squamous cell carcinoma (ESCC) samples that were of a high tumor grade and advanced stage. RNA interference-mediated knockdown of NEFH accelerated ESCC cell growth in culture and increased tumorigenicity in vivo, whereas forced expression of NEFH significantly inhibited cell growth and colony formation. Loss of NEFH caused up-regulation of pyruvate kinase-M2 type and down-regulation of pyruvate dehydrogenase, via activation of the Akt/β-catenin pathway, resulting in enhanced aerobic glycolysis and mitochondrial dysfunction. The acceleration of glycolysis and mitochondrial dysfunction in NEFH-knockdown cells was suppressed in the absence of β-catenin expression, and was decreased by the treatment of 2-Deoxyglucose, a glycolytic inhibitor, or API-2, an Akt inhibitor. Loss of NEFH activates the Akt/β-catenin pathway and increases glycolysis and mitochondrial dysfunction. Cancer cells with methylated NEFH can be targeted for destruction with specific inhibitors of deregulated downstream pathways.
OGDHL Is a Modifier of AKT-Dependent Signaling and NF-κB Function
Tanusree Sen, Nilkantha Sen, Maartje G. Noordhuis, Rajani Ravi, T-C Wu, Patrick K. Ha, David Sidransky, Mohammad Obaidul Hoque
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048770
Abstract: Oxoglutarate dehydrogenase (OGDH) is the first and rate-limiting component of the multi-enzyme OGDH complex (OGDHC) whose malfunction is associated with neuro-degeneration. The essential role of this complex is in the degradation of glucose and glutamate and the OGDHL gene (one component of OGDHC) is down-regulated by promoter hypermethylation in many different cancer types. These properties suggest a potential growth modulating role of OGDHL in cancer; however, the molecular mechanism through which OGDHL exerts its growth modulating function has not been elucidated. Here, we report that restoration of OGDHL expression in cervical cancer cells lacking endogenous OGDHL expression suppressed cell proliferation, invasion and soft agar colony formation in vitro. Knockdown of OGDHL expression in cervical cancer cells expressing endogenous OGDHL had the opposite effect. Forced expression of OGDHL increased the production of reactive oxygen species (ROS) leading to apoptosis through caspase 3 mediated down-regulation of the AKT signaling cascade and decreased NF-κB phosphorylation. Conversely, silencing OGDHL stimulated the signaling pathway via increased AKT phosphorylation. Moreover, the addition of caspase 3 or ROS inhibitors in the presence of OGDHL increased AKT signaling and cervical cancer cell proliferation. Taken together, these data suggest that inactivation of OGDHL can contribute to cervical tumorigenesis via activation of the AKT signaling pathway and thus support it as an important anti-proliferative gene in cervical cancer.
Cysteine Dioxygenase 1 Is a Tumor Suppressor Gene Silenced by Promoter Methylation in Multiple Human Cancers
Mariana Brait, Shizhang Ling, Jatin K. Nagpal, Xiaofei Chang, Hannah Lui Park, Juna Lee, Jun Okamura, Keishi Yamashita, David Sidransky, Myoung Sook Kim
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044951
Abstract: The human cysteine dioxygenase 1 (CDO1) gene is a non-heme structured, iron-containing metalloenzyme involved in the conversion of cysteine to cysteine sulfinate, and plays a key role in taurine biosynthesis. In our search for novel methylated gene promoters, we have analyzed differential RNA expression profiles of colorectal cancer (CRC) cell lines with or without treatment of 5-aza-2′-deoxycytidine. Among the genes identified, the CDO1 promoter was found to be differentially methylated in primary CRC tissues with high frequency compared to normal colon tissues. In addition, a statistically significant difference in the frequency of CDO1 promoter methylation was observed between primary normal and tumor tissues derived from breast, esophagus, lung, bladder and stomach. Downregulation of CDO1 mRNA and protein levels were observed in cancer cell lines and tumors derived from these tissue types. Expression of CDO1 was tightly controlled by promoter methylation, suggesting that promoter methylation and silencing of CDO1 may be a common event in human carcinogenesis. Moreover, forced expression of full-length CDO1 in human cancer cells markedly decreased the tumor cell growth in an in vitro cell culture and/or an in vivo mouse model, whereas knockdown of CDO1 increased cell growth in culture. Our data implicate CDO1 as a novel tumor suppressor gene and a potentially valuable molecular marker for human cancer.
Alterations of GPI transamidase subunits in head and neck squamous carcinoma
Wei-Wen Jiang, Marianna Zahurak, Zeng-Tong Zhou, Hannah Park, Zhong-Min Guo, Guo-Jun Wu, David Sidransky, Barry Trink, Joseph A Califano
Molecular Cancer , 2007, DOI: 10.1186/1476-4598-6-74
Abstract: To evaluate GAA1, PIG-T and PIG-U in HNSCC, we used quantitative PCR (QPCR) and quantitative RT-PCR (QRT-PCR) to determine the copy number of those genes in primary tumors and the matching lymphocytes in 28 patients with HNSCC and quantified RNA expression of those genes in 16 primary HNSCC patients and 4 normal control tissue samples. GAA1 showed a significant increase in normalized mRNA expression, 2.11 (95% CI: 1.43, 2.79), in comparison to that of normal controls, 0.43 (95% CI: -0.76, 1.61), p = 0.014 (Mann-Whitney test). The mean genomic copy number of GAA1 was significantly increased in HNSCC, 0.59 (95% CI: 0.50, 0.79), in comparison to lymphocyte DNA, 0.35 (95% CI: 0.30, 0.50), p = 0.001 (paired t-test).An increased expression level and elevated copy number for GAA1 suggest a role for this GPI anchor subunit in HNSCC.HNSCC has an annual incidence of over than 40,000 cases per year in United States and is characterized by local tumor aggressiveness, a high rate of early recurrences, and development of second primary carcinomas [1]. Despite modern therapeutic strategies, overall 5-year survival rate does have only modestly improved.Glycosylphosphatidylinositol (GPI) anchoring is a membrane attachment mechanism for cell surface proteins widely used in eukaryotes. GPI anchor attachment is catalyzed by GPI transamidase (GPIT) complex, which is composed of at least five subunits: Phosphatidylinositol Glycan Class U (PIG-U), Glycosylphosphatidylinositol Anchor Attachment Protein 1 (GAA1), Phosphatidylinositol Glycan Class K (Gpi8), Phosphatidylinositol Glycan Class S (PIG-S), Phosphatidylinositol Glycan Class T (PIG-T) [2-11]. All of the subunits are required for GPIT to function [3,6-8]. Gpi8 is the likely enzymatic component of the GPIT complex and can be cross-linked to proproteins [5,8,12-14]. GAA1 is able to assemble into PIG-U-containing GPIT complexes that are capable of interacting with a proprotein substrate, and this subunit also is critical in GPI recogni
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