bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 881: A role for microsomal glutathione transferase 1 in melanin biosynthesis in melanoma
Authors: Zhang Jie , Ye Zhi-wei , Townsend Danyelle M. , Morgenstern Ralf , Tew Kenneth D. 
Published: August 2019

Abstract
Higher organisms have multiple defenses against toxic chemical insult, ultraviolet light (UVR) and oxidative stress. These include thioredoxin and glutathione dependent enzymes, some of which are selenium (Se) dependent, including thioredoxin reductases, Se-dependent glutathione peroxidases, Se-independent glutathione transferases and peroxiredoxins. Microsomal glutathione transferase 1 (MGST1) shares an important and unique characteristic with Se-dependent glutathione peroxidase GPX4, namely the ability to reduce lipid hydroperoxides directly in membranes. In contrast to most other glutathione transferases and peroxidases, we previously found that deletion of MGST1 in mice was embryonic lethal, signifying some essential functional importance. We found that MGST1 was crucial for embryonic development through regulating early hematopoiesis in both zebrafish and mouse derived hematopoietic stem cells. Interestingly, after partial knock-down MGST1, the number of melanocytes located at the midline of zebrafish embryos was significantly reduced. Melanocytes are specialized cells that produce melanin, contributing to skin color, but also providing an antioxidant defense system that includes UVR - causative in the initiation of melanoma. Both mRNA and protein levels of MGST1 were markedly decreased in several amelanotic melanoma cell lines and melanogenesis was significantly decreased in B16 melanoma cells when MGST1 expression was knocked down by 60%. This was accompanied by increased UVB-induced cell death in these B16 cells. In contrast, in normal human melanocytes, recombinant adenovirus induced over-expression of MGST1 induced melanogenesis, concomitant with an increase of tyrosinase protein levels. UVB light was used to show that stimulus of melanin biosynthesis occurred in different melanoma cells in quantitative agreement with their levels of MGST1. We conclude that within the melanin synthetic pathway, MGST1 is critical in regulating conversion of dopaquinone to glutathionyl-DOPA, a precursor of pheomelanin. In the absence of MGST1, dopaquinone can cause toxicities and result in reduced or absent levels of melanin, leading to a deficiency in protection against UVR-induced DNA damage. Thus, absence of MGST1 produces embryonic lethality and influences the susceptibility of skin melanocytes to melanoma.
Citation Format: Jie Zhang, Zhi-wei Ye, Danyelle M. Townsend, Ralf Morgenstern, Kenneth D. Tew. A role for microsomal glutathione transferase 1 in melanin biosynthesis in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 881.
Abstract 883: PRDX4 as a novel target for pancreatic cancer
Authors: Jain Pallavi , Sayad Azin , Mollen Erik , Xie Michael , Brown Kevin , Moffat Jason , Hedley David , Boutros Paul , Wouters Bradley , Koritzinsky Marianne 
Published: August 2019

Abstract
Pancreatic cancer (PCa) is a fatal malignancy showing a 5% 5-year survival rate, creating an urgent need for new therapeutic targets. Many cancers have high production of reactive oxygen species (ROS), leaving them potentially vulnerable to targeting proteins involved in ROS metabolism. In line with this, we identified Peroxiredoxin 4 (PRDX4) as an essential gene in 26% of pancreatic cell lines by mining functional genomics datasets. PRDX4 is localized in the endoplasmic reticulum (ER) where it metabolizes H2O2. We validated in nine established PCa cell lines and patient derived primary cell lines that depletion of PRDX4 using siRNA or shRNA leads to inhibition of proliferation and cell death in a subset of pancreatic cancer cells. This was accompanied by increased levels of reactive oxygen species (ROS) as measured by flow cytometry. Dual-Depletion of NADPH oxidase 4 (NOX4) and PRDX4 could rescue the cell death phenotype thereby indicating that increase in ROS was a consequence of NOX4 activity. PRDX4 depletion led to focal accumulation of phosphorylated H2AX (γH2AX) in the cellular nuclei, consistent with DNA damage. Phosphorylation of H2AX was exclusively dependent upon activation of the upstream kinase DNA-PKcs. Cells depleted for PRDX4 were also more sensitive to ionizing radiation. Depleting PRDX4 with inducible shRNA in established xenografts inhibited tumor growth. Finally, using transcriptome data accompanying the functional genomics datasets, we identified a 2-gene expression signature that predicts sensitivity to PRDX4 targeting.
This study indicates that depletion of PRDX4 causes increased ROS resulting in DNA damage leading to DNA-PKcs activation, inhibition of proliferation and cell death in a subset of pancreatic cancers. PRDX4 is a potential novel therapeutic target that may act synergistically with radiation therapy.
Citation Format: Pallavi Jain, Azin Sayad, Erik Mollen, Michael Xie, Kevin Brown, Jason Moffat, David Hedley, Paul Boutros, Bradley Wouters, Marianne Koritzinsky. PRDX4 as a novel target for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 883.
Abstract 885: Induction of PRDX2 by H. pylori reduces ROS and promotes cancer cell survival and resistance to cisplatin
Authors: Wang Sen , Chen Zheng , Lu Heng , Zhu Shoumin , Peng Dunfa , Soutto Mohammed , Gomma Ahmed , Bhat Nadeem , Naz Huma , Xu Zekuan , El-Rifai Wael 
Published: August 2019

Abstract
Background & Aims: The antioxidant enzyme peroxiredoxin 2 (PRDX2) plays a critical role in regulating reactive oxygen species (ROS) levels in several diseases. Helicobacter pylori (H. pylori) infection is a well-known risk factor of gastric cancer. The role of PRDX2 in gastric tumorigenesis remains largely unknown. We investigated the molecular function and regulation of PRDX2 in response to infection with H. pylori and cisplatin treatment in gastric cancer cells.
Methods:Western blots (WB) and quantitative real-time PCR (qPCR) analysis were performed on AGS, SNU-1 and MKN28 gastric cancer cell lines to detect PRDX2 expression levels with or without H. pyloriinfection (7.13 or J166 strain). We evaluated the levels of ROS by H2DCFDA staining. WB analysis was used to determine oxidative DNA damage and double stranded DNA breaks by using antibodies against 8-Oxo-guanine and p-H2AX. WB and NF-κb luciferase reporter assay were performed to investigate the link between PRDX2 and NF-κb signaling. ATP-GLO cell titer analysis was utilized to determine cell viability.
Results:Our data indicated that PRDX2 mRNA and protein expression levels were induced byH. pyloriin AGS and SNU-1 cells. PRDX2 knockdown significantly increased ROS levels and 8-Oxoguanine staining followingH. pyloriinfection in both cells. These results were further confirmed by Western blot data showing that p-H2AX protein level was strongly induced in PRDX2 knockdown and H. pyloriinfected cells. Interestingly, Western blot data showed that TNF-αtreatment induced PRDX2 protein levels while Bay 11-7082 treatment decreased PRDX2 protein level in AGS and SNU-1 cells. At the same time, PRDX2 transient knockdown in both AGS and SNU-1 cells decreased p-P65 (S536) protein expression levels, nuclear localization of NF-κB-p65, and luciferase reporter activity (P&lt;0.05). We also found that inhibition of PRDX2 significantly sensitized AGS and SNU-1 cells to cisplatin treatment.
Conclusion:Our data indicates that knockdown of PRDX2 enhances ROS and DNA damage with H. pylori infection on gastric cancer cells after H. pylori infection and sensitizes gastric cancer cells to cisplatin treatment. Our results suggest a positive feedforward loop between PRDX2 and NF-kB to reduce ROS levels.
KEY WORDS: PRDX2,H. pylori, gastric cancer, reactive oxygen species, DNA damage, NF-κb
Citation Format: Sen Wang, Zheng Chen, Heng Lu, Shoumin Zhu, Dunfa Peng, Mohammed Soutto, Ahmed Gomma, Nadeem Bhat, Huma Naz, Zekuan Xu, Wael El-Rifai. Induction of PRDX2 by H. pylori reduces ROS and promotes cancer cell survival and resistance to cisplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 885.
Abstract 887: Silver nanoparticles and ionizing radiation induce mitochondrial protein oxidation and effects on cell cycle and proliferation in lung cancer cell lines
Authors: Holmila Reetta J. , Vance Stephen A. , Singh Ravi , King S. Bruce , Furdui Cristina M. 
Published: August 2019

Abstract
Silver nanoparticles (AgNP) are widely applied nanomaterials for both commercial and clinical biomedical applications. AgNP have been shown to have cytotoxicity in various cancer cell lines, as well as radiosensitizing properties. The AgNPs may induce free radicals via Fenton-type reactions, but the cellular mechanisms related to reactive oxygen species (ROS) production remain largely unknown. Both ionizing radiation (IR) and AgNP exposure lead to apoptotic and necrotic cell death through mechanisms that involve DNA damage and induction of oxidative stress, possibly targeting mitochondria. Changes in the thiol redox state of mitochondrial proteins, such as protein sulfenylation, play an important role in a number of cellular processes, and mitochondrial damage and dysfunction along with increased mitochondrial ROS are implicated in a range of human diseases such as cancer. In this work we studied the molecular effects of AgNP exposure with and without IR in a panel of lung cell lines (three cancer cell lines: A549, Calu-1 and NCI-H358 and one immortalized lung epithelial cell line: BEAS-2B). Both AgNP and IR exposures increased mitochondrial protein oxidation detected by a recently developed mitochondria targeted probe for protein sulfenylation (DCP-NEt2C). This increase in DCP-NEt2C labeling was dose and time dependent and the exposures also showed a combined effect. Moreover, the exposures induced changes in cell cycle and decreased cellular proliferation. There were marked differences between different cell lines, likely reflecting differences in the cellular redox state and metabolism. In conclusion, the AgNP and IR exposures increase the mitochondrial ROS as demonstrated by increased protein oxidation and have effects on the cell cycle and cell proliferation. They also appear to have a combined effect which might have implications for clinical applications as well as environmental risk assessment.
Citation Format: Reetta J. Holmila, Stephen A. Vance, Ravi Singh, S. Bruce King, Cristina M. Furdui. Silver nanoparticles and ionizing radiation induce mitochondrial protein oxidation and effects on cell cycle and proliferation in lung cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 887.
Abstract 889: Biochemical and histopathological evaluation of Al2O3 nanomaterials in kidney of Wistar rats
Authors: Patlolla Anita , Tchounwou Paul 
Published: August 2019

Abstract
The present study was investigated to evaluate the response of kidneys in Wistar rats following long term exposure to Al2O3 nanomaterials. To achieve this objective, Al2O3 of three different sizes (30nm, 40nm and bulk) was orally administered for 28 days to 9 groups of 10 Wistar rats each at the dose of 500, 1000 and 2000 mg/kg/rat. A tenth group of 10 rats received distilled water and served as control. After 28 days of exposure the animals were sacrificed and the serum was collected and tested for the activity levels of creatinine and urea following standard methods. Induction of oxidative stress was also investigated by assessing TBARS (MDA), Protein carbonyl, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) activities. A Histopathological evaluation was also performed to determine the extent of kidney damage. The results showed that both serum creatinine and serum urea levels increased significantly in the treated rats compared to control animals. The increase was found to be more in Al2O3-30nm followed by Al2O3-40nm and Al2O3-bulk treated rats in a dose-dependent manner. Further administration of Al2O3 significantly increased the activities of TBARS, protein carbonyl, catalase and decreased the activities of GSH and SOD in a dose dependent manner in the kidney of rats compared with control group. Histopathological evaluation showed significant morphological alterations in kidney tissue of treated rats in accordance with biochemical parameters. Taken together, the results of this study demonstrate that Al2O3 is nephrotoxic and its toxicity may be mediated through oxidative stress. Further, the results suggest that prolonged oral exposure to Al2O3 NMs has the potential to cause biochemical and histological alterations in kidney of rats at high concentration.
Note: This abstract was not presented at the meeting.
Citation Format: Anita Patlolla, Paul Tchounwou. Biochemical and histopathological evaluation of Al2O3 nanomaterials in kidney of Wistar rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 889.
Abstract 890: Nuclear factor kappa B (NF-κB) promotes oxidative stress adaptation and survivorship
Authors: White Elshaddai , Carter Jada R. , Hinton Cimona V. 
Published: August 2019

Abstract
Cellular oxidative stress is one of the several hallmarks of the aggressive phenotypes observed in prostate cancer. As levels of reactive oxygen species (ROS) increase, oxidative stressors activate mechanisms allowing cancer cells to adapt and survive. It is unclear how cancer cells adapt and survive oxidative stress; however, literature demonstrates that the transcription factor, nuclear factor-kappa B (NF-κB) contributes to survival during oxidative stress. In cancer, several factors resulting in oxidative stress, including chemotherapy, correlate with NF-κB expression and transcriptional activity, enhancing tumor survivorship and resistance to therapies. We examined adaptability and survivorship to oxidative stress in two common prostate cancer models, DU145 and PC3, which display varying degrees of tumorigenicity, respectively. We observed that serum-starvation induced ROS, stimulating an early oxidative stress environment, and cells further conferred adaptability with the addition of hydrogen peroxide (H202). Measurement of cell viability demonstrated a low death profile in stressed cells, while cell proliferation was stagnant. Quantitative measurement of apoptosis showed no significant cell death in stressed cells suggesting an adaptive mechanism to oxidative stress survival. Consistent with stress adaptation, we observed NF-κB in nuclear fractionations of cell lines which were consistent with nuclear localization observed in other diseases in literature that adapt to oxidative stress. Adaptability to oxidative stress may be a precursor to the inflammatory response in prostate tumor tissues, and/or a general survival mechanism to anti-tumorigenic agents.
Acknowledgements: These studies were supported by the NIH/NIGMS/RISE #5R25GM060414-15 and NIH/NIHMD/RCMI #5G12MD007590.
Citation Format: Elshaddai White, Jada R. Carter, Cimona V. Hinton. Nuclear factor kappa B (NF-κB) promotes oxidative stress adaptation and survivorship [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 890.
Abstract 902: The antiandrogen bicalutamide induces senescence in LNCaP cells and quiescence in Myc CaP cells
Authors: Carpenter Valerie J. , Saleh Tareq , Gewirtz David A. 
Published: August 2019

Abstract
The survival benefits in prostate cancer (PCa) conferred by androgen deprivation therapies (ADT) and antiandrogens are often blunted by the development of castration resistant disease (CRPC). There is increasing evidence that the primary cellular response to ADT is senescence rather than apoptosis, and this may influence progression to CRPC. However, the majority of in vitro studies employ the charcoal stripped serum model, and very few studies use antiandrogens, despite the fact that antiandrogens are currently one of the primary modes of therapy for prostate cancer. In an effort to enhance our understanding of antiandrogen effects in PCa, we evaluated the cellular response to the clinically relevant antiandrogen, bicalutamide, in the human LNCaP and murine Myc-CaP cell lines. Acute treatment (48 hours) with bicalutamide resulted in a growth arrest followed by proliferative recovery in both cell lines. However, while the growth arrest was prolonged (lasting at least 6 days) in the LnCaP cells, growth arrest was exceedingly brief (lasting approximately 24 hours) in the Myc-CaP cells. Consistent with these observations, we were able to detect increased beta galactosidase staining (a hallmark of senescence) in the LnCaP treated cells but not the Myc-CaP treated cells. Despite the fact that profound morphological changes were evident in the Myc-Cap cells, including an enlarged and elongated cell body, the highly transient nature of the growth arrest suggests that the Myc-Cap cells undergo quiescence rather than senescence. The absence of senescence induction in the Myc-CaP cells may be a consequence of the androgen receptor copy number gain. However, androgen duplication is highly uncommon in human prostate cancers prior to development of CRPC. Thus, it is likely that antiandrogens can induce senescence in treatment-naïve patients, as seen in the LNCaP cell line. The ability of bicalutamide to induce senescence, albeit perhaps conditionally, suggests that some prostate cancers treated with ADT and/or antiandrogens may be susceptible to drugs that target senescent cells (senolytics). We therefore propose that elimination of senescent cells prior to recovery could attenuate or prevent the development of CRPC.
Citation Format: Valerie J. Carpenter, Tareq Saleh, David A. Gewirtz. The antiandrogen bicalutamide induces senescence in LNCaP cells and quiescence in Myc CaP cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 902.
Abstract 914: Development of a whole-urine, next-generation sequencing-based assay for early detection of aggressive prostate cancer
Authors: Cani Andi K. , Hu Kevin , Siddiqui Javed , Han Sumin , Hovelson Daniel H. , Liu Chia-Jen , Salami Simpa S. , Palapattu Ganesh S. , Morgan Todd M. , Wei John T. , Chinnaiyan Arul M. , Tomlins Scott A. 
Published: August 2019

Abstract
Despite advances in biomarker development, early detection of aggressive prostate cancer (PCa) remains challenging. Existing biomarkers show modest improvement over models based on serum prostate specific antigen (PSA). We have previously developed a clinical-grade laboratory-developed test, named MiProstate Score (MiPS), for individualized risk prediction of aggressive prostate cancer. It uses transcription-mediated amplification to quantify the gene-fusion TMPRSS2:ERG (T2:ERG) (T1E4 splice isoform) and the lncRNA PCA3 from whole-urine obtained after a digital rectal exam (DRE), combined with serum PSA. To improve MiPS, we describe here the pre-clinical development and validation of a targeted next generation sequencing assay (NGS-MiPS) using post-DRE urine RNA to asses ~90 PCa transcriptomic biomarkers. These include those in MiPS as well as many isoforms of common PCa gene fusions, mRNA, and lncRNA candidate biomarkers nominated by our large-scale PCa tissue RNAseq and other sources. We have obtained a 98% informative sample rate from 2.5 mL of urine and high technical reproducibility (Pearson r=0.99). Risk scores for having PCa [or high-grade PCa (Gleason Score &gt;6)] on biopsy, as determined by clinical MiPS vs. the clinical MiPS model using NGS data, were highly concordant, Pearson’s r=0.74 (and r=0.81). Urine from patients with benign or Gleason 6 vs. Gleason ≥ 4+3=7 cancer on biopsy (extreme design) showed expected differences in the levels of T2:ERG T1E4 (p=0.00003) and PCA3 (p=0.07), with additional T2:ERG splice isoforms and other biomarkers also being significantly different between low vs. high grade cancer. Feature selection and logistic regression trained in an extreme design cohort (n=73) yielded a 29-transcript model that outperformed MiPS and serum PSA in two validation cohorts: 1. A held-out set from the extreme design cohort n=36, AUC 0.81 vs. 0.76 and 0.63 respectively; 2. A separate active surveillance cohort n=45, AUCs 0.66 vs. 0.56 and 0.53 respectively. These results support the potential utility of our urine based targeted NGS assay to supplement serum PSA for the early detection of aggressive prostate cancer.
Citation Format: Andi K. Cani, Kevin Hu, Javed Siddiqui, Sumin Han, Daniel H. Hovelson, Chia-Jen Liu, Simpa S. Salami, Ganesh S. Palapattu, Todd M. Morgan, John T. Wei, Arul M. Chinnaiyan, Scott A. Tomlins. Development of a whole-urine, next-generation sequencing-based assay for early detection of aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 914.