H Phillip Koeffler

Cedars-Sinai Medical Center, Los Ángeles, California, United States

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Publications (780)5477.87 Total impact

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    ABSTRACT: Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation of oncogenes induced immediate cell death in the vast majority of cells. Few surviving pre-B cell clones had acquired permissiveness to oncogenic signaling by strong activation of negative feedback regulation of Erk signaling. Studying negative feedback regulation of Erk in genetic experiments at three different levels, we found that Spry2, Dusp6, and Etv5 were essential for oncogenic transformation in mouse models for pre-B acute lymphoblastic leukemia (ALL). Interestingly, a small molecule inhibitor of DUSP6 selectively induced cell death in patient-derived pre-B ALL cells and overcame conventional mechanisms of drug-resistance. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer cell 06/2015; DOI:10.1016/j.ccell.2015.05.008 · 23.89 Impact Factor
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    ABSTRACT: Molecular targeted therapy is an important approach for advanced hepatocellular carcinoma (HCC). Hepatitis B virus-related HCC (HBV-HCC) accounts for approximately 50% of all HCC cases. Bortezomib, a proteasome inhibitor, is used extensively for the treatment of hematologic malignancies, but its application in HCC, particularly in HBV-HCC, has not been fully explored. The effects of bortezomib on HCC tissues were evaluated by TUNEL assays. The growth inhibitory activity was measured using cell viability assays, and apoptosis was measured using flow cytometry. The levels of HBx, P-Raf/Raf and P-Erk/Erk expression were measured by Western blot. The ability of the MEK inhibitor PD98059 to enhance the cell killing activity of bortezomib was evaluated using ex vivo and in vivo methods. The potency of bortezomib varied among HCC samples and cell lines, and HBV/HBx expression was associated with resistance to bortezomib. Bortezomib increased the levels of P-Raf and P-Erk in HBV/HBx-positive cells but not in HBV/HBx-negative HCC cells or in breast cancer or glioblastoma multiform cells. HBx was also upregulated after exposure to bortezomib, which was associated with the inhibition of proteasome activity. P-Erk upregulation mediated by bortezomib was effectively suppressed by the addition of the MEK inhibitor PD98059. Moreover, bortezomib and PD98059 synergistically inhibited HCC cell proliferation, as measured using both ex vivo and in vivo models. Our studies demonstrate for the first time that HBx causes resistance to bortezomib in HCC, and this resistance can be antagonized by a MEK signaling inhibitor, providing a novel therapeutic approach. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 06/2015; DOI:10.1158/1078-0432.CCR-14-2067 · 8.19 Impact Factor
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    ABSTRACT: Neutrophil-specific granule deficiency (SGD) is a rare autosomal recessive primary immunodeficiency characterized by neutrophil dysfunction, bilobed neutrophil nuclei and lack of neutrophil-specific granules. Defects in a myeloid-specific transcription factor, CCAAT/enhancer binding protein-ε (C/EBPε), have been identified in two cases in which homozygous frameshift mutations led to loss of the leucine zipper domain. In this study, we report a 55-y-old woman affected with SGD caused by a novel homozygous 2-aa deletion (ΔRS) in the leucine zipper domain of the C/EBPε gene. The patient showed characteristic neutrophil abnormalities and recurrent skin infections; however, there was no history of deep organ infections. Biochemical analysis revealed that, in contrast to the two frameshift mutations, the ΔRS mutant maintained normal cellular localization, DNA-binding activity, and dimerization, and all three mutants exhibited marked reduction in transcriptional activity. The ΔRS mutant was defective in its association with Gata1 and PU.1, as well as aberrant cooperative transcriptional activation of eosinophil major basic protein. Thus, the ΔRS likely impairs protein-protein interaction with other transcription factors, resulting in a loss of transcriptional activation. These results further support the importance of the leucine zipper domain of C/EBPε for its essential function, and indicate that multiple molecular mechanisms lead to SGD. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 05/2015; DOI:10.4049/jimmunol.1402222 · 5.36 Impact Factor
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    ABSTRACT: Next generation sequencing technologies have provided insights into the molecular heterogeneity of various myeloid neoplasms, revealing previously unknown somatic genetic events. In our cohort of 1444 cases analyzed by next generation sequencing, somatic mutations in the gene BRCA1-BRCA2-containing complex 3 (BRCC3) were identified in 28 cases (1.9%). BRCC3 is a member of the JAMM/MPN+ family of zinc metalloproteases capable of cleaving Lys-63 linked polyubiquitin chains, and is implicated in DNA repair. The mutations were located throughout its coding region. The average variant allelic frequency of BRCC3 mutations was 30.1%, and by a serial sample analysis at two different time points a BRCC3 mutation was already identified in the initial stage of a myelodysplastic syndrome. BRCC3 mutations commonly occurred in nonsense (n=12), frameshift (n=4), and splice site (n=5) configurations. Due to the marginal male dominance (odds ratio; 2.00, 0.84-4.73) of BRCC3 mutations, the majority of mutations (n=23; 82%) were hemizygous. Phenotypically, BRCC3 mutations were frequently observed in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms and associated with -Y abnormality (odds ratio; 3.70, 1.25-11.0). Clinically, BRCC3 mutations were also related to higher age (p=0.01), although prognosis was not affected. Knock-down of Brcc3 gene expression in murine bone marrow lineage negative, Sca1 positive, c-kit positive cells resulted in 2-fold more colony formation and modest differentiation defect. Thus, BRCC3 likely plays a role as tumor-associated gene in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Copyright © 2015, Ferrata Storti Foundation.
    Haematologica 05/2015; DOI:10.3324/haematol.2014.111989 · 5.87 Impact Factor
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    ABSTRACT: PARK2 (PARKIN) is an E3 ubiquitin ligase whose dysfunction has been associated with the progression of Parkinsonism and human malignancies, and its role in cancer remains to be explored. In this study, we report that PARK2 is frequently deleted and underexpressed in human glioma, and low PARK2 expression is associated with poor survival. Restoration of PARK2 significantly inhibited glioma cell growth both in vitro and in vivo, whereas depletion of PARK2 promoted cell proliferation. PARK2 attenuated both Wnt- and EGF-stimulated pathways through downregulating the intracellular level of beta-catenin and EGFR. Notably, PARK2 physically interacted with both beta-catenin and EGFR. We further found that PARK2 promoted the ubiquitination of these two proteins in an E3 ligase activity-dependent manner. Finally, inspired by these newly identified tumor-suppressive functions of PARK2, we tested and proved that combination of small-molecule inhibitors targeting both Wnt-beta-catenin and EGFR-AKT pathways synergistically impaired glioma cell viability. Together, our findings uncover novel cancer-associated functions of PARK2 and provide a potential therapeutic approach to treat glioma. Cancer Res; 75(9); 1-13. (c)2015 AACR.
    Cancer Research 04/2015; DOI:10.1158/0008-5472.CAN-14-1433 · 9.28 Impact Factor
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    ABSTRACT: We investigated the oncogenic role of SETDB1 focusing on non-small cell lung cancer (NSCLC) having high expression of this protein. A total of 387 lung cancer cases were examined by immunohistochemistry, 72% of NSCLC samples were positive for SETDB1 staining, compared to 46% samples of normal bronchial epithelium (106 cases) (p < 0.0001). Percent positive cells and intensity of staining increased significantly with increased grade of disease. Forced expression of SETDB1 in NSCLC cell lines enhanced their clonogenic growth in vitro and markedly increased tumor size in a murine xenograft model; while silencing (shRNA) SETDB1 in NSCLC cells slowed their proliferation. SETDB1 positively stimulated activity of the WNT/beta-catenin pathway and diminished P53 expression resulting in enhanced NSCLC growth in vitro and in vivo. Our finding suggests therapeutic targeting SETDB1 may benefit patients whose tumors express high levels of SETDB1.
    The Journal of Pathology 03/2015; DOI:10.1002/path.4482 · 7.33 Impact Factor
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    ABSTRACT: 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) and vitamin D receptor (VDR) have been reported to have an important role in the regulation of innate immunity. We earlier reported that the antimicrobial peptide cathelicidin is induced by 1,25(OH)2D3 in normal human bronchial epithelial cells with a resultant increase in antimicrobial activity against airway pathogens. In this study we demonstrate that C/EBP alpha (C/EBPα) is a potent enhancer of human cathelicidin antimicrobial peptide (CAMP) gene transcription in human lung epithelial cells. In addition we found that C/EBPα functionally cooperates with VDR in the regulation of CAMP transcription. A C/EBP binding site was identified at -627/-619 within the CAMP promoter, adjacent to the vitamin D response element (VDRE; -615/-600). Mutation of this site markedly attenuated the transcriptional response to C/EBPα as well as to 1,25(OH)2D3, further indicating cooperation between these two factors in the regulation of CAMP. ChIP analysis using 1,25(OH)2D3 treated human lung epithelial cells showed C/EBPα and VDR binding to the CAMP promoter. C/EBPα has previously been reported to cooperate with Brahma (Brm), an ATPase that is component of the SWI/SNF chromatin remodeling complex. We found that dominant negative Brm significantly inhibited C/EBPα as well as 1,25(OH)2D3 mediated induction of CAMP transcription, suggesting the functional involvement of Brm. These findings define novel mechanisms involving C/EBPα, SWI/SNF and 1,25(OH)2D3 in the regulation of CAMP in lung epithelial cells. These mechanisms of enhanced activation of the CAMP gene in lung epithelial cells suggest potential candidates for the development of modulators of innate immune responses for adjunct therapy in the treatment of airway infections. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 02/2015; 230(2). DOI:10.1002/jcp.24729 · 3.87 Impact Factor
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    ABSTRACT: We utilized three tiers of screening to identify novel therapeutic agents for pancreatic cancers. First, we analyzed 14 pancreatic cancer cell lines against a panel of 66 small-molecule kinase inhibitors and dasatinib was the most potent. Second, we performed RNA expression analysis on 3 dasatinib-resistant and 3 dasatinib?sensitive pancreatic cancer cell lines to profile their gene expression. Third, gene profiling data was integrated with the connectivity map database to search for potential drugs. Thioridazine was one of the top ranking small molecules with highly negative enrichment. Thioridazine and its family members of phenothiazine including penfludidol caused pancreatic cancer cell death and affected protein expression levels of molecules involved in cell cycle regulation, apoptosis, and multiple kinase activities. This family of drugs causes activation of protein phosphatase 2 (PP2A). The drug FTY-720 (activator of PP2A) induced apoptosis of pancreatic cancer cells. Silencing catalytic unit of PP2A rendered pancreatic cancer cells resistant to penfluridol. Our observations suggest potential therapeutic use of penfluridol or similar agent associated with activation of PP2A in pancreatic cancers.
    Molecular Oncology 01/2015; DOI:10.1016/j.molonc.2015.01.002 · 5.94 Impact Factor
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    ABSTRACT: Somatic mutations in the spliceosome gene ZRSR2-located on the X chromosome-are associated with myelodysplastic syndrome (MDS). ZRSR2 is involved in the recognition of 3'-splice site during the early stages of spliceosome assembly; however, its precise role in RNA splicing has remained unclear. Here we characterize ZRSR2 as an essential component of the minor spliceosome (U12 dependent) assembly. shRNA-mediated knockdown of ZRSR2 leads to impaired splicing of the U12-type introns and RNA-sequencing of MDS bone marrow reveals that loss of ZRSR2 activity causes increased mis-splicing. These splicing defects involve retention of the U12-type introns, while splicing of the U2-type introns remain mostly unaffected. ZRSR2-deficient cells also exhibit reduced proliferation potential and distinct alterations in myeloid and erythroid differentiation in vitro. These data identify a specific role for ZRSR2 in RNA splicing and highlight dysregulated splicing of U12-type introns as a characteristic feature of ZRSR2 mutations in MDS.
    Nature Communications 01/2015; 6:6042. DOI:10.1038/ncomms7042 · 10.74 Impact Factor
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    ABSTRACT: Studies have reported that the CCN family of proteins plays an important role in stimulating tumorigenesis. However, the relationship between the CCN protein family members and the features of hepatocellular carcinoma (HCC) remains unclear. The objective of this study was to determine the relationship between the expression levels of CCN protein family members and the features of HCC. Expression levels of the CCN family of proteins in 80-paired primary HCC samples and 11 normal liver samples were determined by a quantitative real-time PCR assay. Enhanced expression of nephroblastoma overexpressed protein (NOV) and decreased expression of Wnt-induced secreted protein 1 (WISP1), cysteine-rich protein 61 (CYR61) and connective tissue growth factor (CTGF) were found in HCC samples when compared to levels in matched non-cancerous tissues. No significant difference in WISP2 was found between matched-pair samples; only a few samples showed WISP3 expression. Furthermore, the expression levels of NOV, WISP1 and CYR61 were closely correlated with certain clinical features, including venous invasion, cellular differentiation, pTNM stage, disease-free survival and overall survival. Our results suggest that HCC progression may be enhanced by NOV and suppressed by WISP1 and CYR61. Our statistical analysis suggests that these proteins may be valuable in determining the prognosis of this deadly disease and directs attention to modulating the levels of these proteins as a potential mode of therapy.
    Oncology Reports 01/2015; 33(3). DOI:10.3892/or.2015.3709 · 2.19 Impact Factor
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    ABSTRACT: Somatic mutations of the epidermal growth factor receptor often cause resistance to therapy with tyrosine kinase inhibitor in non-small cell lung cancer (NSCLC). In this study, we aimed to identify partner drugs and pathways that can induce cell death in combination with gefitinib in NSCLC cells. We undertook a genome-wide RNAi screen to identify synthetic lethality with gefitinib in tyrosine kinase inhibitor resistant cells. The screening data were utilized in different approaches. Firstly, we identified PRKCSH as a candidate gene, silencing of which induces apoptosis of NSCLC cells treated with gefitinib. Next, in an in silico gene signature pathway analysis of shRNA library data, a strong correlation of genes involved in the CD27 signaling cascade was observed. We showed that the combination of dasatinib (NF-κB pathway inhibitor) with gefitinib synergistically inhibited the growth of NSCLC cells. Lastly, utilizing the Connectivity Map, thioridazine was identified as a top pharmaceutical perturbagen. In our experiments, it synergized with gefitinib to reduce p-Akt levels and to induce apoptosis in NSCLC cells. Taken together, a pooled short-hairpin library screen identified several potential pathways and drugs that can be therapeutic targets for gefitinib resistant NSCLC.
    Oncotarget 11/2014; · 6.63 Impact Factor
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    ABSTRACT: Context: Anaplastic thyroid cancer (ATC) has no effective treatment, resulting in a high rate of mortality. We established cell lines from a primary ATC and its lymph node metastasis, and investigated the molecular factors and genomic changes associated with tumor growth. Objective: The aim of the study was to understand the molecular and genomic changes of highly aggressive ATC and its clonal evolution to develop rational therapies. Design: We established unique cell lines from primary (OGK-P) and metastatic (OGK-M) ATC specimen, as well as primagraft from the metastatic ATC, which was serially xeno-transplanted for more than 1 year in NSG mice were established. These cell lines and primagraft were used as tools to examine gene expression, copy number changes, and somatic mutations using RNA array, SNP Chip, and whole exome sequencing. Results: Mice carrying subcutaneous (OGK-P and OGK-M) tumors developed splenomegaly and neutrophilia with high expression of cytokines including CSF1, CSF2, CSF3, IL-1β, and IL-6. Levels of HIF-1α and its targeted genes were also elevated in these tumors. The treatment of tumor carrying mice with Bevacizumab effectively decreased tumor growth, macrophage infiltration, and peripheral WBCs. SNP chip analysis showed homozygous deletion of exons 3-22 of the PARD3 gene in the cells. Forced expression of PARD3 decreased cell proliferation, motility, and invasiveness, restores cell-cell contacts and enhanced cell adhesion. Next generation exome sequencing identified the somatic changes present in the primary, metastatic, and primagraft tumors demonstrating evolution of the mutational signature over the year of passage in vivo. Conclusion: To our knowledge, we established the first paired human primary and metastatic ATC cell lines offering unique possibilities for comparative functional investigations in vitro and in vivo. Our exome sequencing also identified novel mutations, as well as clonal evolution in both the metastasis and primagraft.
    Journal of Clinical Endocrinology &amp Metabolism 11/2014; 100(2):jc20142359. DOI:10.1210/jc.2014-2359 · 6.31 Impact Factor
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    ABSTRACT: The use of genome-wide copy-number analysis and massive parallel sequencing has revolutionized the understanding of the clonal architecture of pediatric acute lymphoblastic leukemia (ALL) by demonstrating that this disease is composed of highly variable clonal ancestries following the rules of Darwinian selection. The current study aimed to analyze the molecular composition of childhood ALL biopsies and patient-derived xenografts with particular emphasis on mechanisms associated with acquired chemoresistance. Genomic DNA from seven primary pediatric ALL patient samples, 29 serially passaged xenografts, and six in vivo selected chemoresistant xenografts were analyzed with 250,000 single-nucleotide polymorphism arrays. Copy-number analysis of non-drug-selected xenografts confirmed a highly variable molecular pattern of variegated subclones. Whereas primary patient samples from initial diagnosis displayed a mean of 5.7 copy-number alterations per sample, serially passaged xenografts contained a mean of 8.2 and chemoresistant xenografts a mean of 10.5 copy-number alterations per sample, respectively. Resistance to cytarabine was explained by a new homozygous deletion of the DCK gene, whereas methotrexate resistance was associated with monoallelic deletion of FPGS and mutation of the remaining allele. This study demonstrates that selecting for chemoresistance in xenografted human ALL cells can reveal novel mechanisms associated with drug resistance. Copyright © 2014 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.
    Experimental Hematology 10/2014; 43(1). DOI:10.1016/j.exphem.2014.09.007 · 2.81 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):510-510. DOI:10.1158/1538-7445.AM2014-510 · 9.28 Impact Factor
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    ABSTRACT: Bromodomain and extra terminal domain (BET) proteins are important epigenetic regulators facilitating the transcription of genes in chromatin areas linked to acetylated histones. JQ1, a BET protein inhibitor, has antiproliferative activity against many cancers, mainly through inhibition of c-MYC and upregulation of p21. In this research, we investigated the use of JQ1 for human osteosarcoma (OS) treatment. JQ1 significantly inhibited the proliferation and survival of OS cells inducing G1 cell cycle arrest, premature senescence, but little effect on apoptosis. Interestingly, c-MYC protein levels in JQ1-treated cells remained unchanged, whereas the upregulation of p21 protein was still observable. Although effective in vitro, JQ1 alone failed to reduce the size of the MNNG/HOS xenografts in immunocompromised mice. To overcome the resistance of OS cells to JQ1 treatment, we combined JQ1 with rapamycin, an mTOR inhibitor. JQ1 and rapamycin synergistically inhibited the growth and survival of OS cells in vitro and in vivo. We also identified that RUNX2 is a direct target of BRD4 inhibition by JQ1 in OS cells. Chromatin immunoprecipitation (ChIP) showed that enrichment of BRD4 protein around RUNX2 transcription start sites diminished with JQ1 treatment in MNNG/HOS cells. Overexpression of RUNX2 protected JQ1-sensitive OS cells from the effect of JQ1, and siRNA-mediated inhibition of RUNX2 sensitized the same cells to JQ1. In conclusion, our findings suggest that JQ1, in combination with rapamycin, is an effective chemotherapeutic option for OS treatment. We also show that inhibition of RUNX2 expression by JQ1 partly explains the antiproliferative activity of JQ1 in OS cells. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 10/2014; 136(9). DOI:10.1002/ijc.29269 · 5.01 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):5542-5542. DOI:10.1158/1538-7445.AM2014-5542 · 9.28 Impact Factor
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    ABSTRACT: Pancreatic ductal adenocarcinoma is a devastating disease with few therapeutic options. Histone deacetylase inhibitors are a novel therapeutic approach to cancer treatment; and two new pan-histone deacetylase inhibitors (HDACi), belinostat and panobinostat, are undergoing clinical trials for advanced hematologic malignancies, non-small cell lung cancers and advanced ovarian epithelial cancers. We found that belinostat and panobinostat potently inhibited, in a dose-dependent manner, the growth of six (AsPc1, BxPc3, Panc0327, Panc0403, Panc1005, MiaPaCa2) of 14 human pancreatic cancer cell lines. Belinostat increased the percentage of apoptotic pancreatic cancer cells and caused prominent G2 /M growth arrest of most pancreatic cancer cells. Belinostat prominently inhibited PI3K-mTOR-4EBP1 signaling with a 50% suppression of phorphorylated 4EBP1 (AsPc1, BxPc3, Panc0327, Panc1005 cells). Surprisingly, belinostat profoundly blocked hypoxia signaling including the suppression of hypoxia response element reporter activity; as well as an approximately 10-fold decreased transcriptional expression of VEGF, adrenomedullin, and HIF1α at 1% compared to 20% O2 . Treatment with this HDACi decreased levels of thioredoxin mRNA associated with increased levels of its endogenous inhibitor thioredoxin binding protein-2. Also, belinostat alone and synergistically with gemcitabine significantly (P = 0.0044) decreased the size of human pancreatic tumors grown in immunodeficiency mice. Taken together, HDACi decreases growth, increases apoptosis, and is associated with blocking the AKT/mTOR pathway. Surprisingly, it blocked hypoxic growth related signals. Our studies of belinostat suggest it may be an effective drug for the treatment of pancreatic cancers when used in combination with other drugs such as gemcitabine. © 2013 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 09/2014; 53(9). DOI:10.1002/mc.22024 · 4.77 Impact Factor
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    ABSTRACT: BackgroundStudies from our laboratory and others have shown that cysteine-rich 61 (Cyr61) may be involved in tumor proliferation and invasion. In earlier studies, we demonstrated increased insulin-like growth factor-I (IGF-1) is associated with breast tumor formation and poor clinical outcomes. In our current study we have investigated IGF-1 regulation of Cyr61 and whether targeting IGF-1 could inhibit Cyr61 induced tumor growth and proliferation.MethodsSeveral ATCC derived normal and breast cancer cell lines were used in this study: MDA-MB231, BT474, MCF-7, and SKBR3. We also tested cells stably transfected in our laboratory with active Akt1 (pAkt; SKBR3/AA and MCF-7/AA) and dominant negative Akt1 (SKBR3/DN and MCF-7/DN). In addition, we used MCF-7 cells transfected with full length Cyr61 (CYA). Monolayer cultures treated with IGF-1 were analyzed for Cyr61 expression by RT-PCR and immunohistochemical staining. Migration assays and MTT based proliferation assays were used to determine invasive characteristics in response to IGF-1/Cyr61 activation.ResultsCells with activated Akt have increased levels of Cyr61. Conversely, cells with inactive Akt have decreased levels of Cyr61. IGF-1 treatment increased Cyr61 expression significantly and cells with high level of Cyr61 demonstrate increased invasiveness and proliferation. Cyr61 overexpression and activation led to decrease in E-cadherin and decrease in FOXO1. Inhibition of the PI3K and MAPK pathways resulted in significant decrease in invasiveness and proliferation, most notably in the PI3K pathway inhibited cells.ConclusionThe findings of this study show that IGF-1 upregulates Cyr61 primarily through activation of the Akt-PI3K pathway. IGF-1 induced MAPK plays a partial role. Increase in Cyr61 leads to increase in breast cancer cell growth and invasion. Hence, targeting Cyr61 and associated pathways may offer an opportunity to inhibit IGF-1 mediated Cyr61 induced breast cancer growth and invasion.
    PLoS ONE 07/2014; 9(7):e103534. DOI:10.1371/journal.pone.0103534 · 3.53 Impact Factor
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    ABSTRACT: Exportin-1 (XPO1, CRM1) mediates the nuclear export of several key growth regulatory and tumor suppressor proteins. Cancer cells often overexpress XPO1 resulting in cytoplasmic mislocalization and aberrant activity of its target proteins. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to and inhibit the function of XPO1 have been recently developed. The aim of this study was to investigate the efficacy of the clinical staged, orally available, SINE compound, KPT-330 in hepatocellular carcinoma (HCC).
    Cancer Chemotherapy and Pharmacology 07/2014; 74(3). DOI:10.1007/s00280-014-2495-8 · 2.57 Impact Factor

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33k Citations
5,477.87 Total Impact Points

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  • 1991–2015
    • Cedars-Sinai Medical Center
      • • Cedars Sinai Medical Center
      • • Division of Hematology and Oncology
      • • Department of Medicine
      Los Ángeles, California, United States
  • 1981–2015
    • University of California, Los Angeles
      • • Division of Hematology and Medical Oncology
      • • Department of Medicine
      • • Center for Culture and Health
      Los Ángeles, California, United States
  • 2014
    • National University of Singapore
      Tumasik, Singapore
    • National University (California)
      San Diego, California, United States
  • 2013
    • National University Cancer Institute
      Tumasik, Singapore
  • 2009–2013
    • The University of Tokyo
      Tōkyō, Japan
    • Universität Heidelberg
      • Department of Hematology / Oncology
      Heidelburg, Baden-Württemberg, Germany
    • Mayo Clinic - Rochester
      Рочестер, Minnesota, United States
    • Kanazawa University
      • Department of Stem Cell Biology
      Kanazawa, Ishikawa, Japan
  • 2012
    • Universitätsklinikum Münster
      Muenster, North Rhine-Westphalia, Germany
  • 2007–2012
    • Shanghai Institutes for Biological Sciences
      Shanghai, Shanghai Shi, China
    • Kawasaki Medical University
      Kurasiki, Okayama, Japan
  • 2004–2011
    • Kochi University
      • Department of Hematology and Respiratory Medicine
      Kôti, Kōchi, Japan
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
    • Vanderbilt University
      • Department of Biochemistry
      Nashville, Michigan, United States
    • Institut Pasteur
      Lutetia Parisorum, Île-de-France, France
  • 1977–2009
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      • Department of Medicine
      Torrance, California, United States
  • 1986–2008
    • CSU Mentor
      • Department of Medicine
      Long Beach, California, United States
  • 2006
    • University of Kentucky
      • Department of Pharmaceutical Sciences
      Lexington, Kentucky, United States
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 2003–2006
    • Kagawa University
      • Faculty of Medicine
      Takamatu, Kagawa, Japan
    • University of Toronto
      • Department of Paediatrics
      Toronto, Ontario, Canada
  • 1993–2006
    • Keio University
      • • Department of Internal Medicine
      • • School of Medicine
      Edo, Tōkyō, Japan
  • 1991–2006
    • Kochi Medical School
      Kôti, Kōchi, Japan
  • 2005
    • IT University of Copenhagen
      København, Capital Region, Denmark
    • University of New Mexico
      Albuquerque, New Mexico, United States
    • Oita University
      Ōita, Ōita, Japan
    • The University of Edinburgh
      Edinburgh, Scotland, United Kingdom
    • Charles R. Drew University of Medicine and Science
      • Internal Medicine
      Los Ángeles, California, United States
  • 2000–2003
    • University of Münster
      • Department of Medicine, Hematology and Oncology
      Münster, North Rhine-Westphalia, Germany
    • University of Michigan
      Ann Arbor, Michigan, United States
    • University of Illinois at Chicago
      • Department of Surgical Oncology (Chicago)
      Chicago, IL, United States
  • 2001
    • Showa University
      Shinagawa, Tōkyō, Japan
    • Shinshu University
      • Department of Pediatrics
      Shonai, Nagano, Japan
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
  • 1999
    • Keck School of Medicine USC
      Los Angeles, California, United States
    • Hiroshima University
      • Medical Research Institute for Bio Functions
      Hiroshima-shi, Hiroshima-ken, Japan
  • 1998
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 1995–1998
    • National Institute of Radiological Sciences
      Tiba, Chiba, Japan
    • Nippon Medical School
      • Nippon Medical School Hospital
      Edo, Tōkyō, Japan
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
  • 1997
    • Wistar Institute
      Philadelphia, Pennsylvania, United States
    • Fred Hutchinson Cancer Research Center
      Seattle, Washington, United States
    • Truman Medical Center
      Kansas City, Kansas, United States
    • City of Hope National Medical Center
      Дуарте, California, United States
  • 1996
    • Cincinnati Children's Hospital Medical Center
      Cincinnati, Ohio, United States
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 1990
    • Stanford University
      • Department of Medicine
      Palo Alto, California, United States
  • 1988–1990
    • University of California, Riverside
      • • Division of Biomedical Sciences
      • • Department of Biochemistry
      Riverside, CA, United States
  • 1989
    • Baylor College of Medicine
      Houston, Texas, United States
  • 1988–1989
    • Harbor-UCLA Medical Center
      Torrance, California, United States