27 results on '"Ouyang, Xuesong"'
Search Results
2. Preclinical pharmacology modeling of chimeric antigen receptor T therapies
- Author
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Kumari, Rajendra, Ouyang, Xuesong, Wang, Jingjing, Xu, Xiaoxi, Zheng, Meiling, An, Xiaoyu, and Li, Qi-Xiang
- Published
- 2021
- Full Text
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3. Composition and Histone Substrates of Polycomb Repressive Group Complexes Change during Cellular Differentiation
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Kuzmichev, Andrei, Margueron, Raphael, Vaquero, Alejandro, Preissner, Tanja S., Scher, Michael, Kirmizis, Antonis, Ouyang, Xuesong, Brockdorff, Neil, Abate-Shen, Cory, Farnham, Peggy, Reinberg, Danny, and Roeder, Robert G.
- Published
- 2005
4. A Critical Role for p27kip1 Gene Dosage in a Mouse Model of Prostate Carcinogenesis
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Gao, Hui, Ouyang, Xuesong, Banach-Petrosky, Whitney, Borowsky, Alexander D., Lin, Yong, Kim, Minjung, Lee, Hansol, Shih, Weichung-Joseph, Cardiff, Robert D., Shen, Michael M., Abate-Shen, Cory, and Yamamoto, Keith R.
- Published
- 2004
5. Identification of an NKX3.1-G9a-UTY transcriptional regulatory network that controls prostate differentiation
- Author
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Dutta, Aditya, Le Magnen, Clémentine, Mitrofanova, Antonina, Ouyang, Xuesong, Califano, Andrea, and Abate-Shen, Cory
- Published
- 2016
6. A living biobank of matched pairs of patient-derived xenografts and organoids for cancer pharmacology.
- Author
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Xu, Xiaoxi, Kumari, Rajendra, Zhou, Jun, Chen, Jing, Mao, Binchen, Wang, Jingjing, Zheng, Meiling, Tu, Xiaolong, An, Xiaoyu, Chen, Xiaobo, Zhang, Likun, Tian, Xiaoli, Wang, Haojie, Dong, Xin, Bao, Zhengzheng, Guo, Sheng, Ouyang, Xuesong, Shang, Limei, Wang, Fei, and Yan, Xuefei
- Subjects
CELL culture ,DRUG discovery ,CANCER stem cells ,PHARMACOLOGY ,XENOGRAFTS ,ORGANOIDS - Abstract
Patient-derived tumor xenograft (PDX)/organoid (PDO), driven by cancer stem cells (CSC), are considered the most predictive models for translational oncology. Large PDX collections reflective of patient populations have been created and used extensively to test various investigational therapies, including population-trials as surrogate subjects in vivo. PDOs are recognized as in vitro surrogates for patients amenable for high-throughput screening (HTS). We have built a biobank of carcinoma PDX-derived organoids (PDXOs) by converting an existing PDX library and confirmed high degree of similarities between PDXOs and parental PDXs in genomics, histopathology and pharmacology, suggesting "biological equivalence or interchangeability" between the two. Here we demonstrate the applications of PDXO biobank for HTS "matrix" screening for both lead compounds and indications, immune cell co-cultures for immune-therapies and engineering enables in vitro/in vivo imaging. This large biobank of >550 matched pairs of PDXs/PDXOs across different cancers could become powerful tools for the future cancer drug discovery. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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- View/download PDF
7. Combinatorial Activities of Akt and B-Raf/Erk Signaling in a Mouse Model of Androgen-Independent Prostate Cancer
- Author
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Gao, Hui, Ouyang, Xuesong, Banach-Petrosky, Whitney A., Gerald, William L., Shen, Michael M., and Abate-Shen, Cory
- Published
- 2006
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8. Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model
- Author
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Kinkade, Carolyn Waugh, Castillo-Martin, Mireia, Puzio-Kuter, Anna, Yan, Jun, Foster, Thomas H., Gao, Hui, Sun, Yvonne, Ouyang, Xuesong, Gerald, William L., Cordon-Cardo, Carlos, and Abate-Shen, Cory
- Subjects
Prostate cancer -- Risk factors -- Diagnosis -- Care and treatment -- Prognosis ,Chemotherapy -- Health aspects ,Cancer -- Chemotherapy ,Health care industry - Abstract
The AKT/mamnialian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and upregulated expression of the apoptotic regulator Bcl-2-interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease., Introduction Prostate cancer is one of the most common neoplasms, particularly among aging males in the United States. Like many adenocarcinomas, prostate tumors arise from preinvasive lesions, mainly prostatic intraepithelial [...]
- Published
- 2008
9. Inhibition of telomerase in tumor cells by ribozyme targeting telomerase RNA component
- Author
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Liu, Bailin, Qu, Yi, Liu, Shuqiu, and Ouyang, Xuesong
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- 2002
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10. Microarray and bioinformatic detection of novel and established genes expressed in experimental anti-Thy1 nephritis
- Author
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SADLIER, DENISE M., OUYANG, XUESONG, MCMAHON, BLAITHIN, MU, WEI, OHASHI, RYUJI, RODGERS, KAREN, MURRAY, DAVID, NAKAGAWA, TAKAHIKO, GODSON, CATHERINE, DORAN, PETER, BRADY, HUGH R., and JOHNSON, RICK J.
- Published
- 2005
11. BRAF Activation Initiates but Does Not Maintain Invasive Prostate Adenocarcinoma.
- Author
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Jeong, Joseph H., Zhenxiong Wang, Guimaraes, Alexander S., Ouyang, Xuesong, Figueiredo, Jose L., Zhihu Ding, Shan Jiang, Guney, Isil, Gyeong Hoon Kang, Eyoung Shin, Hahn, William C., Loda, Massimo F., Abate-Shen, Cory, Weissleder, Ralph, and Chin, Lynda
- Subjects
ADENOCARCINOMA ,PROSTATE cancer ,ANDROGENS ,FOCAL adhesion kinase ,MELANOMA ,SEX hormones ,PHENOL oxidase ,SPONTANEOUS cancer regression ,CARCINOGENESIS - Abstract
Prostate cancer is the second leading cause of cancer-related deaths in men. Activation of MAP kinase signaling pathway has been implicated in advanced and androgen-independent prostate cancers, although formal genetic proof has been lacking. In the course of modeling malignant melanoma in a tyrosinase promoter transgenic system, we developed a genetically-engineered mouse (GEM) model of invasive prostate cancers, whereby an activating mutation of BRAF
V600E -a mutation found in ,10% of human prostate tumors-was targeted to the epithelial compartment of the prostate gland on the background of Ink4a/Arf deficiency. These GEM mice developed prostate gland hyperplasia with progression to rapidly growing invasive adenocarcinoma without evidence of AKT activation, providing genetic proof that activation of MAP kinase signaling is sufficient to drive prostate tumorigenesis. Importantly, genetic extinction of BRAFV600E in established prostate tumors did not lead to tumor regression, indicating that while sufficient to initiate development of invasive prostate adenocarcinoma, BRAFV600E is not required for its maintenance. [ABSTRACT FROM AUTHOR]- Published
- 2008
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12. Experimental animal modeling for immuno-oncology.
- Author
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Li, Qi-Xiang, Feuer, Gerold, Ouyang, Xuesong, and An, Xiaoyu
- Subjects
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ANIMAL models in research , *ONCOLOGY , *IMMUNE response , *ANTINEOPLASTIC agents , *PHARMACEUTICAL industry - Abstract
Immuno-oncology (I/O) research has intensified significantly in recent years due to the breakthrough development and the regulatory approval of several immune checkpoint inhibitors, leading to the rapid expansion of the new discovery of novel I/O therapies, new checkpoint inhibitors and beyond. However, many I/O questions remain unanswered, including why only certain subsets of patients respond to these treatments, who the responders would be, and how to expand patient response (the conversion of non-responders or maximizing response in partial responders). All of these require relevant I/O experimental systems, particularly relevant preclinical animal models. Compared to other oncology drug discovery, e.g . cytotoxic and targeted drugs, a lack of relevant animal models is a major obstacle in I/O drug discovery, and an urgent and unmet need. Despite the obvious importance, and the fact that much I/O research has been performed using many different animal models, there are few comprehensive and introductory reviews on this topic. This article attempts to review the efforts in development of a variety of such models, as well as their applications and limitations for readers new to the field, particularly those in the pharmaceutical industry. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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13. Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model.
- Author
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Waugh Kinkade, Carolyn, Castillo-Martin, Mireia, Puzio-Kuter, Anna, Jun Yan, Foster, Thomas H., Hui Gao, Yvonne Sun, Xuesong Ouyang, Gerald, William L., Cordon-Cardo, Carlos, Abate-Shen, Cory, Kinkade, Carolyn Waugh, Yan, Jun, Gao, Hui, Sun, Yvonne, and Ouyang, Xuesong
- Subjects
- *
UROLOGY , *PROSTATE cancer , *GENITOURINARY diseases , *LABORATORY rats , *CANCER cells , *CELL lines , *CELL culture - Abstract
The AKT/mammalian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and upregulated expression of the apoptotic regulator Bcl-2-interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
14. Editor's Note: Activator Protein-1 Transcription Factors Are Associated with Progression and Recurrence of Prostate Cancer.
- Author
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Ouyang X, Jessen WJ, Al-Ahmadie H, Serio AM, Lin Y, Shih WJ, Reuter VE, Scardino PT, Shen MM, Aronow BJ, Vickers AJ, Gerald WL, and Abate-Shen C
- Published
- 2023
- Full Text
- View/download PDF
15. Creating Matched In vivo/In vitro Patient-Derived Model Pairs of PDX and PDX-Derived Organoids for Cancer Pharmacology Research.
- Author
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Xu X, Shang L, Wang P, Zhou J, Ouyang X, Zheng M, Mao B, Zhang L, Chen B, Wang J, Chen J, Qian W, Guo S, Huang Y, and Li QX
- Subjects
- Animals, Disease Models, Animal, Humans, Mice, Pharmacology, Antineoplastic Agents, Neoplasms, Organoids, Xenograft Model Antitumor Assays
- Abstract
Patient-derived tumor xenografts (PDXs) are considered the most predictive preclinical models, largely believed to be driven by cancer stem cells (CSC) for conventional cancer drug evaluation. A large library of PDXs is reflective of the diversity of patient populations and thus enables population based preclinical trials ("Phase II-like mouse clinical trials"); however, PDX have practical limitations of low throughput, high costs and long duration. Tumor organoids, also being patient-derived CSC-driven models, can be considered as the in vitro equivalent of PDX, overcoming certain PDX limitations for dealing with large libraries of organoids or compounds. This study describes a method to create PDX-derived organoids (PDXO), thus resulting in paired models for in vitro and in vivo pharmacology research. Subcutaneously-transplanted PDX-CR2110 tumors were collected from tumor-bearing mice when the tumors reached 200-800 mm
3 , per an approved autopsy procedure, followed by removal of the adjacent non-tumor tissues and dissociation into small tumor fragments. The small tumor fragments were washed and passed through a 100 µm cell strainer to remove the debris. Cell clusters were collected and suspended in basement membrane extract (BME) solution and plated in a 6-well plate as a solid droplet with surrounding liquid media for growth in a CO2 incubator. Organoid growth was monitored twice weekly under light microscopy and recorded by photography, followed by liquid medium change 2 or 3 times a week. The grown organoids were further passaged (7 days later) at a 1:2 ratio by disrupting the BME embedded organoids using mechanical shearing, aided by addition of trypsin and the addition of 10 µM Y-27632. Organoids were cryopreserved in cryo-tubes for long-term storage, after release from BME by centrifugation, and also sampled (e.g., DNA, RNA and FFPE block) for further characterization.- Published
- 2021
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16. In Vivo Pharmacology Models for Cancer Target Research.
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Chen D, An X, Ouyang X, Cai J, Zhou D, and Li QX
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- Animals, Antineoplastic Agents therapeutic use, Carcinogenesis drug effects, Carcinogenesis genetics, Carcinogenesis pathology, Cell Line, Tumor, Humans, Mice, Molecular Targeted Therapy methods, Neoplasms genetics, Neoplasms pathology, Neoplasms, Experimental drug therapy, Neoplasms, Experimental genetics, Neoplasms, Experimental pathology, Transgenes, Tumor Burden drug effects, Antineoplastic Agents pharmacology, Drug Discovery methods, Gene Targeting methods, Neoplasms drug therapy, Xenograft Model Antitumor Assays methods
- Abstract
Experimental animal tumor models have been broadly used to evaluate anticancer drugs in the preclinical setting. They have also been widely applied for drug target discovery and validation, which usually follows four experimental strategies: first, assess the roles of putative drug targets using in vivo tumorigenicity and tumor growth kinetics assays of transplanted tumors, engineered through gain-of-function (GOF) by overexpressing transgene or knock-in (KI) or loss-of-function by gene silencing using knockdown (KD) or knockout (KO) or mutation via mutagenesis procedures; second, similarly genetically engineered mouse models (GEMM), through either germline or somatic cell procedures, are used to test the roles of potential targets in spontaneous tumorigenicity assays; third, patient-derived xenografts (PDXs), which most closely resemble patient genetics and histopathology, are used in tumor inhibition assays for evaluating target-/pathway-specific inhibitors, including large and small molecules, thus assessing the drug target; and fourth, the targets can be assessed in population-based trials, mouse clinical trials (MCT), so that the validation can be generally meaningful as performed in human clinical trials. This chapter outlines the commonly used protocols in cancer drug target research: the first four sections describe four sets of different, specific pharmacology protocols used in the respective cancer modeling stages, with the last section summarizing the common protocols applicable to all four pharmacology modeling steps.
- Published
- 2019
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17. Immunophenotyping of Orthotopic Homograft (Syngeneic) of Murine Primary KPC Pancreatic Ductal Adenocarcinoma by Flow Cytometry.
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An X, Ouyang X, Zhang H, Li T, Huang YY, Li Z, Zhou D, and Li QX
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- Allografts, Animals, Flow Cytometry, Immunophenotyping, Mice, Inbred C57BL, Mice, Transgenic, Transplantation, Homologous, Tumor Microenvironment immunology, Adenocarcinoma immunology, Carcinoma, Pancreatic Ductal immunology, Pancreatic Neoplasms immunology
- Abstract
Homograft (syngeneic) tumors are the workhorse of today's immuno-oncology (I/O) preclinical research. The tumor microenvironment (TME), particularly its immune-components, is vital to the prognosis and prediction of treatment outcomes, especially those of immunotherapy. TME immune-components are composed of different subsets of tumor-infiltrating immune cells assessable by multi-color FACS. Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest malignances lacking good treatment options, thus an urgent and unmet medical need. One important reason for its non-responsiveness to various therapies (chemo-, targeted, I/O) has been its abundant TME, consisting of fibroblasts and leukocytes that protect tumor cells from these therapies. Orthotopically implanted PDAC is believed to more accurately recapture the TME of human pancreatic cancers than conventional subcutaneous (SC) models. Homograft tumors (KPC) are transplants of mouse spontaneous PDAC originating from genetically engineered KPC-mice (Kras
G12D/+ /P53-/- /Pdx1-Cre) (KPC-GEMM). The primary tumor tissue is cut into small fragments (~2 mm3 ) and transplanted subcutaneously (SC) to the syngeneic recipients (C57BL/6, 7-9 weeks old). The homografts were then surgically orthotopically transplanted onto the pancreas of new C57BL/6 mice, along with SC-implantation, which reached tumor volumes of 300-1,000 mm3 by 17 days. Only tumors of 400-600 mm3 were harvested per approved autopsy procedure and cleaned to remove the adjacent non-tumor tissues. They were dissociated per protocol using a tissue dissociator into single-cell suspensions, followed by staining with designated panels of fluorescently-labeled antibodies for various markers of different immune cells (lymphoid, myeloid and NK, DCs). The stained samples were analyzed using multi-color FACS to determine numbers of immune cells of different lineages, as well as their relative percentage within tumors. The immune profiles of orthotopic tumors were then compared to those of SC tumors. The preliminary data demonstrated significantly elevated infiltrating TILs/TAMs in tumors over the pancreas, and higher B-cell infiltration into orthotopic rather than SC tumors.- Published
- 2018
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18. Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice.
- Author
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Hastings NB, Wang X, Song L, Butts BD, Grotz D, Hargreaves R, Fred Hess J, Hong KK, Huang CR, Hyde L, Laverty M, Lee J, Levitan D, Lu SX, Maguire M, Mahadomrongkul V, McEachern EJ, Ouyang X, Rosahl TW, Selnick H, Stanton M, Terracina G, Vocadlo DJ, Wang G, Duffy JL, Parker EM, and Zhang L
- Subjects
- Animals, Mice, Mice, Transgenic, Protein Processing, Post-Translational, Pyrans pharmacology, Thiazoles pharmacology, Tauopathies metabolism, beta-N-Acetylhexosaminidases antagonists & inhibitors, tau Proteins metabolism
- Abstract
Background: Hyperphosphorylation of microtubule-associated protein tau is a distinct feature of neurofibrillary tangles (NFTs) that are the hallmark of neurodegenerative tauopathies. O-GlcNAcylation is a lesser known post-translational modification of tau that involves the addition of N-acetylglucosamine onto serine and threonine residues. Inhibition of O-GlcNAcase (OGA), the enzyme responsible for the removal of O-GlcNAc modification, has been shown to reduce tau pathology in several transgenic models. Clarifying the underlying mechanism by which OGA inhibition leads to the reduction of pathological tau and identifying translatable measures to guide human dosing and efficacy determination would significantly facilitate the clinical development of OGA inhibitors for the treatment of tauopathies., Methods: Genetic and pharmacological approaches are used to evaluate the pharmacodynamic response of OGA inhibition. A panel of quantitative biochemical assays is established to assess the effect of OGA inhibition on pathological tau reduction. A "click" chemistry labeling method is developed for the detection of O-GlcNAcylated tau., Results: Substantial (>80%) OGA inhibition is required to observe a measurable increase in O-GlcNAcylated proteins in the brain. Sustained and substantial OGA inhibition via chronic treatment with Thiamet G leads to a significant reduction of aggregated tau and several phosphorylated tau species in the insoluble fraction of rTg4510 mouse brain and total tau in cerebrospinal fluid (CSF). O-GlcNAcylated tau is elevated by Thiamet G treatment and is found primarily in the soluble 55 kD tau species, but not in the insoluble 64 kD tau species thought as the pathological entity., Conclusion: The present study demonstrates that chronic inhibition of OGA reduces pathological tau in the brain and total tau in the CSF of rTg4510 mice, most likely by directly increasing O-GlcNAcylation of tau and thereby maintaining tau in the soluble, non-toxic form by reducing tau aggregation and the accompanying panoply of deleterious post-translational modifications. These results clarify some conflicting observations regarding the effects and mechanism of OGA inhibition on tau pathology, provide pharmacodynamic tools to guide human dosing and identify CSF total tau as a potential translational biomarker. Therefore, this study provides additional support to develop OGA inhibitors as a treatment for Alzheimer's disease and other neurodegenerative tauopathies.
- Published
- 2017
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19. Nuclear Export of Ubiquitinated Proteins Determines the Sensitivity of Colorectal Cancer to Proteasome Inhibitor.
- Author
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Wu T, Chen W, Zhong Y, Hou X, Fang S, Liu CY, Wang G, Yu T, Huang YY, Ouyang X, Li HQ, Cui L, and Yang Y
- Subjects
- Active Transport, Cell Nucleus drug effects, Animals, Antineoplastic Agents pharmacology, Bortezomib pharmacology, Cell Line, Tumor, Cell Survival drug effects, Colorectal Neoplasms metabolism, Drug Synergism, HCT116 Cells, HeLa Cells, Humans, Hydrazines administration & dosage, Hydrazines pharmacology, Mice, Proteasome Inhibitors pharmacology, Triazoles administration & dosage, Triazoles pharmacology, Ubiquitination drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents administration & dosage, Bortezomib administration & dosage, Cell Nucleus metabolism, Colorectal Neoplasms drug therapy, Proteasome Inhibitors administration & dosage, Tumor Suppressor Protein p53 metabolism
- Abstract
Although proteasome inhibitors such as bortezomib had significant therapeutic effects in multiple myeloma and mantel cell lymphoma, they exhibited minimal clinical activity as a monotherapy for solid tumors, including colorectal cancer. We found in this study that proteasome inhibition induced a remarkable nuclear exportation of ubiquitinated proteins. Inhibition of CRM1, the nuclear export carrier protein, hampered protein export and synergistically enhanced the cytotoxic action of bortezomib on colon cancer cells containing wild-type p53, which underwent G
2 -M cell-cycle block and apoptosis. Further analysis indicated that tumor suppressor p53 was one of the proteins exported from nuclei upon proteasome inhibition, and in the presence of CRM1 inhibitor KPT330, nuclear p53, and expression of its target genes were increased markedly. Moreover, knockdown of p53 significantly reduced the synergistic cytotoxic action of bortezomib and KPT330 on p53+/+ HCT116 cells. In mice, KPT330 markedly augmented the antitumor action of bortezomib against HCT116 xenografts as well as patient-derived xenografts that harbored functional p53. These results indicate that nuclear p53 is a major mediator in the synergistic antitumor effect of bortezomib and KPT330, and provides a rationale for the use of proteasome inhibitor together with nuclear export blocker in the treatment of colorectal cancer. It is conceivable that targeting nuclear exportation may serve as a novel strategy to overcome resistance and raise chemotherapeutic efficacy, especially for the drugs that activate the p53 system. Mol Cancer Ther; 16(4); 717-28. ©2016 AACR ., (©2016 American Association for Cancer Research.)- Published
- 2017
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20. Analysis of tau post-translational modifications in rTg4510 mice, a model of tau pathology.
- Author
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Song L, Lu SX, Ouyang X, Melchor J, Lee J, Terracina G, Wang X, Hyde L, Hess JF, Parker EM, and Zhang L
- Subjects
- Animals, Biomarkers analysis, Brain pathology, Disease Models, Animal, Humans, Mice, Transgenic, Protein Processing, Post-Translational physiology, Tauopathies genetics, Brain metabolism, Protein Processing, Post-Translational genetics, Tauopathies metabolism, tau Proteins genetics, tau Proteins metabolism
- Abstract
Background: Microtubule associated protein tau is the major component of the neurofibrillary tangles (NFTs) found in the brains of patients with Alzheimer's disease and several other neurodegenerative diseases. Tau mutations are associated with frontotemperal dementia with parkinsonism on chromosome 17 (FTDP-17). rTg4510 mice overexpress human tau carrying the P301L FTDP-17 mutation and develop robust NFT-like pathology at 4-5 months of age. The current study is aimed at characterizing the rTg4510 mice to better understand the genesis of tau pathology and to better enable the use of this model in drug discovery efforts targeting tau pathology., Results: Using a panel of immunoassays, we analyzed the age-dependent formation of pathological tau in rTg4510 mice and our data revealed a steady age-dependent accumulation of pathological tau in the insoluble fraction of brain homogenates. The pathological tau was associated with multiple post-translational modifications including aggregation, phosphorylation at a wide variety of sites, acetylation, ubiquitination and nitration. The change of most tau species reached statistical significance at the age of 16 weeks. There was a strong correlation between the different post-translationally modified tau species in this heterogeneous pool of pathological tau. Total tau in the cerebrospinal fluid (CSF) displayed a multiphasic temporal profile distinct from the steady accumulation of pathological tau in the brain. Female rTg4510 mice displayed significantly more aggressive accumulation of pathological tau in the brain and elevation of total tau in CSF than their male littermates., Conclusion: The immunoassays described here were used to generate the most comprehensive description of the changes in various tau species across the lifespan of the rTg4510 mouse model. The data indicate that development of tauopathy in rTg4510 mice involves the accumulation of a pool of pathological tau that carries multiple post-translational modifications, a process that can be detected well before the histological detection of NFTs. Therapeutic treatment targeting tau should therefore aim to reduce all tau species associated with the pathological tau pool rather than reduce specific post-translational modifications. There is still much to learn about CSF tau in physiological and pathological processes in order to use it as a translational biomarker in drug discovery.
- Published
- 2015
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21. Diacylglycerol acyltransferase-1 (DGAT1) inhibition perturbs postprandial gut hormone release.
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Lin HV, Chen D, Shen Z, Zhu L, Ouyang X, Vongs A, Kan Y, Levorse JM, Kowalik EJ Jr, Szeto DM, Yao X, Xiao J, Chen S, Liu J, Garcia-Calvo M, Shin MK, and Pinto S
- Subjects
- Animals, Base Sequence, Diacylglycerol O-Acyltransferase deficiency, Diacylglycerol O-Acyltransferase metabolism, Diet, Dipeptidyl Peptidase 4 genetics, Dipeptidyl Peptidase 4 metabolism, Dogs, Enzyme Activation, Female, Gastric Emptying genetics, Gene Dosage, Gene Expression Regulation, Gene Order, Genotype, Glucagon-Like Peptide 1 metabolism, Lipid Metabolism, Male, Mice, Mice, Knockout, Molecular Sequence Data, Triglycerides blood, Diacylglycerol O-Acyltransferase genetics, Gastrointestinal Hormones metabolism, Gastrointestinal Tract metabolism, Postprandial Period
- Abstract
Diacylglycerol acyltransferase-1 (DGAT1) is a potential therapeutic target for treatment of obesity and related metabolic diseases. However, the degree of DGAT1 inhibition required for metabolic benefits is unclear. Here we show that partial DGAT1 deficiency in mice suppressed postprandial triglyceridemia, led to elevations in glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) only following meals with very high lipid content, and did not protect from diet-induced obesity. Maximal DGAT1 inhibition led to enhanced GLP-1 and PYY secretion following meals with physiologically relevant lipid content. Finally, combination of DGAT1 inhibition with dipeptidyl-peptidase-4 (DPP-4) inhibition led to further enhancements in active GLP-1 in mice and dogs. The current study suggests that targeting DGAT1 to enhance postprandial gut hormone secretion requires maximal inhibition, and suggests combination with DPP-4i as a potential strategy to develop DGAT1 inhibitors for treatment of metabolic diseases.
- Published
- 2013
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22. Attenuation of Slc27a5 gene expression followed by LC-MS measurement of bile acid reconjugation using metabolomics and a stable isotope tracer strategy.
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Castro-Perez JM, Roddy TP, Shah V, Wang SP, Ouyang X, Ogawa A, McLaren DG, Tadin-Strapps M, Robinson MJ, Bartz SR, Ason B, Chen Y, Previs SF, Wong KK, Vreeken RJ, Johns DG, Hubbard BK, Hankemeier T, and Mitnaul L
- Subjects
- Animals, Gene Silencing, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Spectrometry, Mass, Electrospray Ionization, Bile Acids and Salts metabolism, Chromatography, Liquid methods, Fatty Acid Transport Proteins metabolism, Liver pathology, Mass Spectrometry methods, Metabolomics methods
- Abstract
The purpose of this study was to evaluate the use of high resolution LC-MS together with metabolomics and D(4)-cholic acid (D(4)-CA) as a metabolic tracer to measure the metabolism and reconjugation of bile acids (BAs) in vitro and in vivo. Metabolic tracers are very important because they allow for the direct detection (substrate-to-product) of small and significant biological perturbations that may not be apparent when monitoring "static" endogenous levels of particular metabolites. Slc27a5, also known as fatty acid transport protein 5 (FATP5), is the hepatic BA-CoA ligase involved in reconjugating BAs during enterohepatic BA recycling. Using Slc27a5-cKD mice, silencing of ∼90% gene expression was achieved followed by reduction in the reconjugation of D(4)-CA to D(4)-taurocholic acid (D(4)-TCA), as well as other conjugated BA metabolites in plasma (p = 0.0031). The method described allowed a rapid measure of many D(4) and endogenous BA. Analysis of bile resulted in the detection of 39 BA metabolites from a 13 min analytical run. Finally, the utilization of a novel high resolution mass spectrometry method in combination with metabolomics and a stable isotope metabolic tracer allowed for the detection of targeted and untargeted BAs following silencing of the Slc27a5 gene in primary hepatocytes and in mice.
- Published
- 2011
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23. Activator protein-1 transcription factors are associated with progression and recurrence of prostate cancer.
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Ouyang X, Jessen WJ, Al-Ahmadie H, Serio AM, Lin Y, Shih WJ, Reuter VE, Scardino PT, Shen MM, Aronow BJ, Vickers AJ, Gerald WL, and Abate-Shen C
- Subjects
- Animals, Disease Models, Animal, Disease Progression, Enzyme Activation, Epidermal Growth Factor metabolism, Gene Expression Profiling, Gene Expression Regulation, Neoplastic genetics, Homeodomain Proteins genetics, MAP Kinase Signaling System, Male, Mice, Mice, Mutant Strains, Mitogen-Activated Protein Kinase Kinases metabolism, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local metabolism, Neoplasm Recurrence, Local pathology, Oncogene Protein p65(gag-jun) biosynthesis, Oncogene Protein p65(gag-jun) metabolism, PTEN Phosphohydrolase genetics, Prostatic Neoplasms metabolism, Proto-Oncogene Proteins c-fos biosynthesis, Proto-Oncogene Proteins c-fos metabolism, Transcription Factor AP-1 biosynthesis, Transcription Factor AP-1 metabolism, Transcription Factors genetics, Oncogene Protein p65(gag-jun) genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Proto-Oncogene Proteins c-fos genetics, Transcription Factor AP-1 genetics
- Abstract
To identify biomarkers that discriminate the aggressive forms of prostate cancer, we performed gene expression profiling of prostate tumors using a genetically engineered mouse model that recapitulates the stages of human prostate cancer, namely Nkx3.1; Pten mutant mice. We observed a significant deregulation of the epidermal growth factor and mitogen-activated protein kinase (MAPK) signaling pathways, as well as their major downstream effectors--the activator protein-1 transcription factors c-Fos and c-Jun. Forced expression of c-Fos and c-Jun in prostate cancer cells promotes tumorigenicity and results in activation of extracellular signal-regulated kinase (Erk) MAPK signaling. In human prostate cancer, up-regulation of c-Fos and c-Jun proteins occurs in advanced disease and is correlated with Erk MAPK pathway activation, whereas high levels of c-Jun expression are associated with disease recurrence. Our analyses reveal a hitherto unappreciated role for AP-1 transcription factors in prostate cancer progression and identify c-Jun as a marker of high-risk prostate cancer. This study provides a striking example of how accurate mouse models can provide insights on molecular processes involved in progression and recurrence of human cancer.
- Published
- 2008
- Full Text
- View/download PDF
24. Prolonged exposure to reduced levels of androgen accelerates prostate cancer progression in Nkx3.1; Pten mutant mice.
- Author
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Banach-Petrosky W, Jessen WJ, Ouyang X, Gao H, Rao J, Quinn J, Aronow BJ, and Abate-Shen C
- Subjects
- Androgens metabolism, Animals, Disease Progression, Male, Mice, Mice, Inbred C57BL, Neoplasms, Hormone-Dependent metabolism, Neoplasms, Hormone-Dependent pathology, Orchiectomy, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Testosterone Propionate pharmacology, Androgens deficiency, Homeodomain Proteins genetics, Neoplasms, Hormone-Dependent genetics, PTEN Phosphohydrolase genetics, Prostatic Neoplasms genetics, Transcription Factors genetics
- Abstract
In this report, we have investigated the relationship between androgen levels and prostate tumorigenesis in Nkx3.1; Pten mutant mice, a genetically engineered mouse model of human prostate cancer. By experimentally manipulating serum levels of testosterone in these mice for an extended period (i.e., 7 months), we have found that prolonged exposure of Nkx3.1; Pten mutant mice to androgen levels that are 10-fold lower than normal (the "Low-T" group) resulted in a marked acceleration of prostate tumorigenesis compared with those exposed to androgen levels within the reference range (the "Normal-T" group). We found that prostate tumors from the Low-T mutant mice share a similar gene expression profile as androgen-independent prostate tumors from these mutant mice, which includes the deregulated expression of several genes that are up-regulated in human hormone-refractory prostate cancer, such as Vav3 and Runx1. We propose that exposure to reduced androgens may promote prostate tumorigenesis by selecting for molecular events that promote more aggressive, hormone-refractory tumors.
- Published
- 2007
- Full Text
- View/download PDF
25. Vitamin D inhibits the formation of prostatic intraepithelial neoplasia in Nkx3.1;Pten mutant mice.
- Author
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Banach-Petrosky W, Ouyang X, Gao H, Nader K, Ji Y, Suh N, DiPaola RS, and Abate-Shen C
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma pathology, Animals, Bone Density Conservation Agents therapeutic use, Disease Models, Animal, Homeodomain Proteins genetics, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, Nude, PTEN Phosphohydrolase genetics, Prostatic Intraepithelial Neoplasia pathology, Prostatic Neoplasms genetics, Transcription Factors genetics, Homeodomain Proteins physiology, Mutation, PTEN Phosphohydrolase physiology, Precancerous Conditions prevention & control, Prostatic Intraepithelial Neoplasia prevention & control, Prostatic Neoplasms pathology, Transcription Factors physiology, Vitamin D therapeutic use
- Abstract
Purpose: Epidemiologic studies have shown that reduced levels of vitamin D represent a major risk factor for prostate cancer. In this report, we have examined the efficacy of 1alpha,25-dihydroxyvitamin D(3) (1,25 D(3)) as a chemopreventive agent using Nkx3.1; Pten mutant mice, which recapitulate stages of prostate carcinogenesis from prostate intraepithelial neoplasia (PIN) to adenocarcinoma., Experimental Design: 1,25 D(3) (or vehicle) was delivered continuously to Nkx3.1; Pten mutant or control mice for a 4-month period beginning before (precancerous cohort) or after (cancerous cohort) these mice developed PIN. At the conclusion of the study, the mice were analyzed for the occurrence of PIN and/or cancer phenotypes by histologic analyses and immunostaining using known markers of cancer progression in these mice., Results: We found that sustained delivery of 1,25 D(3) to the Nkx3.1; Pten mutant mice resulted in a significant reduction in the formation of PIN while having no apparent effect on the control mice. Furthermore, 1,25 D(3) was maximally effective when delivered before, rather than subsequent to, the initial occurrence of PIN. We further show that this 1,25 D(3)-mediated inhibition of PIN was coincident with up-regulation of vitamin D receptor expression in the prostatic epithelium of the mutant mice, as well as in CASP prostate epithelial cell lines developed from these mice, while having no effect on androgen receptor expression or androgen receptor signaling., Conclusion: Our findings show the value of chemoprevention studies using Nkx3.1; Pten mutant mice, particularly for evaluating the efficacy and underlying mechanisms of potential agents and to gain insights about the optimal timing of their delivery. In particular, our study predicts that vitamin D may have differential effects during early-stage versus late-stage disease and that it is more likely to be beneficial if delivered either before the overt manifestation of clinically detectable disease or during the earliest disease stages, rather than in advanced disease. Thus, our findings support the assessment of vitamin D analogues for chemoprevention in clinical trials targeting patients with early-stage disease and also establish molecular markers that can be used in such trials to determine biological activity and to optimize further clinical trials.
- Published
- 2006
- Full Text
- View/download PDF
26. Emergence of androgen independence at early stages of prostate cancer progression in Nkx3.1; Pten mice.
- Author
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Gao H, Ouyang X, Banach-Petrosky WA, Shen MM, and Abate-Shen C
- Subjects
- Aging, Androgens deficiency, Animals, Cell Division, Cell Survival, Epithelial Cells cytology, Male, Mice, Mice, Mutant Strains, Neoplasm Staging, Orchiectomy, Prostate cytology, Androgens physiology, Homeodomain Proteins genetics, Mutation, PTEN Phosphohydrolase genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Transcription Factors genetics
- Abstract
Although androgen deprivation therapy is a widely used treatment for patients with advanced prostate cancer, it ultimately results in the emergence of a hormone-refractory disease that is invariably fatal. To provide insights into the genesis of this disease, we have employed an in vivo model to investigate how and when prostate epithelial cells can acquire the ability to survive and proliferate in the absence of androgens. In particular, we have been studying the evolution of androgen independence in Nkx3.1; Pten mutant mice, which develop prostatic intraepithelial neoplasia and adenocarcinoma as a consequence of aging, as well as androgen-independent phenotypes following castration. We now find that the prostate epithelial cells from these Nkx3.1; Pten mutant mice are capable of surviving and proliferating in the absence of androgens and that they develop androgen-independent phenotypes well before they display overt prostatic intraepithelial neoplasia or cancer phenotypes. Our findings in this mouse model show that acquisition of androgen independence can be uncoupled from overt cancer progression and raise the possibility that hormone-refractory disease can arise at early stages of prostate carcinogenesis.
- Published
- 2006
- Full Text
- View/download PDF
27. Loss-of-function of Nkx3.1 promotes increased oxidative damage in prostate carcinogenesis.
- Author
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Ouyang X, DeWeese TL, Nelson WG, and Abate-Shen C
- Subjects
- Animals, Antioxidants metabolism, Cell Transformation, Neoplastic metabolism, DNA metabolism, DNA Damage, Gene Expression Profiling, Gene Expression Regulation, Gene Expression Regulation, Neoplastic, Glutathione Peroxidase biosynthesis, Glutathione Peroxidase genetics, Homeodomain Proteins genetics, Male, Mice, Mice, Inbred C57BL, Mutation, Oxidative Stress genetics, Peroxidases biosynthesis, Peroxidases genetics, Peroxiredoxin VI, Peroxiredoxins, Prostate enzymology, Prostate metabolism, Prostate physiology, Prostatic Neoplasms enzymology, Prostatic Neoplasms metabolism, Transcription Factors deficiency, Transcription Factors genetics, Cell Transformation, Neoplastic genetics, Homeodomain Proteins physiology, Prostatic Neoplasms genetics, Transcription Factors physiology
- Abstract
Despite the significance of oxidative damage for carcinogenesis, the molecular mechanisms that lead to increased susceptibility of tissues to oxidative stress are not well-understood. We now report a link between loss of protection against oxidative damage and loss-of-function of Nkx3.1, a homeobox gene that is known to be required for prostatic epithelial differentiation and suppression of prostate cancer. Using gene expression profiling, we find that Nkx3.1 mutant mice display deregulated expression of several antioxidant and prooxidant enzymes, including glutathione peroxidase 2 and 3 (GPx2 and GPx3), peroxiredoxin 6 (Prdx6), and sulfyhydryl oxidase Q6 (Qscn6). Moreover, the formation of prostatic intraepithelial neoplasia in these mutant mice is associated with increased oxidative damage of DNA, as evident by increased levels of 8-hydroxy-2'-deoxyguanosine. We further show that progression to prostate adenocarcinoma, as occurs in compound mutant mice lacking Nkx3.1 as well as the Pten tumor suppressor, is correlated with a further deregulation of antioxidants, including superoxide dismutase enzymes, and more profound accumulations of oxidative damage to DNA and protein, the latter manifested by increased levels of 4-hydroxynonenal. We propose that the essential role of Nkx3.1 in maintaining the terminally differentiated state of the prostate epithelium provides protection against oxidative damage and, thereby, suppression of prostate cancer. Thus, our findings provide a molecular link between a gene whose inactivation is known to be involved in prostate carcinogenesis, namely Nkx3.1, and oxidative damage of the prostatic epithelium.
- Published
- 2005
- Full Text
- View/download PDF
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