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The effects of the histone deacetylase inhibitor romidepsin (FK228) are enhanced by aspirin (ASA) in COX-1 positive ovarian cancer cells through augmentation of p21.
Son DS, Wilson AJ, Parl AK, Khabele D
(2010) Cancer Biol Ther 9: 928-35
MeSH Terms: Aspirin, Blotting, Western, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Cyclooxygenase 1, Depsipeptides, Dose-Response Relationship, Drug, Drug Synergism, Female, Gene Expression Regulation, Neoplastic, Histone Deacetylase Inhibitors, Humans, Ovarian Neoplasms, Proteasome Endopeptidase Complex, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added March 5, 2014
Histone deacetylase (HDAC) inhibitors have shown preclinical efficacy in solid tumors, including ovarian cancers. Our group has published that the HDAC inhibitor, romidepsin (FK228) suppresses ovarian cancer cell growth at nanomolar concentrations in vitro. HDAC inhibitors appear to be even more effective when used in combination with other antitumor agents. However, it remains unclear which antitumor agents are best suited for combination therapy. A recent report suggested that aspirin (acetylsalicylic acid, ASA ) is synergistic with HDAC inhibitors in ovarian cancer cells. ASA is a relatively selective inhibitor of cyclooxygenase-1 (COX-1) and has anti-proliferative effects in ovarian cancer cells. The goal of this study was to investigate the impact of ASA on the activity of the HDAC inhibitor, FK228 in COX-1 positive (OVCAR-3) and COX-1 negative (SKOV-3) human ovarian cancer cell lines. The growth inhibitory effects of FK228 were enhanced by ASA in COX-1 positive ovarian cancer cells. In contrast, ASA had no influence on the results of FK228 treatment in COX-1 negative ovarian cancer cells. Upregulation of the cell cycle control protein p21 was induced robustly by FK228 in both cell lines. In the COX-1 positive cells, p21 expression was augmented by the addition of ASA to FK228 treatment. Furthermore, COX-1 siRNA attenuated the effects of combined ASA and FK228 on the levels of p21 expression and the amount of growth inhibition. The additional increase in p21 by ASA in FK228-treated cells was not observed at the promoter or transcriptional levels. However, a significant delay in p21 protein degradation in the presence of ASA and FK228 in COX-1 positive cells was associated with inhibition of proteasome activity. Our study provides a potential rationale for combining ASA with HDAC inhibitors in a subset of ovarian cancers.
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18 MeSH Terms
Regulation of G(1) arrest and apoptosis in hypoxia by PERK and GCN2-mediated eIF2alpha phosphorylation.
Liu Y, László C, Liu Y, Liu W, Chen X, Evans SC, Wu S
(2010) Neoplasia 12: 61-8
MeSH Terms: Animals, Apoptosis, Blotting, Western, Cell Hypoxia, Cell Survival, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p21, Embryo, Mammalian, Eukaryotic Initiation Factor-2, Fibroblasts, G1 Phase, Mice, Mice, Knockout, Phosphorylation, Protein-Serine-Threonine Kinases, Tumor Suppressor Protein p53, eIF-2 Kinase
Show Abstract · Added June 14, 2013
Hypoxia is a common microenvironment in solid tumors and is correlated with tumor progression by regulating cancer cell survival. Recent studies suggest that activation of double-stranded RNA-dependent protein kinase-like endoplasmic reticulum-related kinase (PERK) and phosphorylation of alpha subunit of eIF2 (eIF2alpha) confer cell adaptation to hypoxic stress. However, eIF2alpha is still phosphorylated at a lowered level in PERK knockout cells under hypoxic conditions. The mechanism for eIF2alpha kinase(s) (eIF2AK)-increased cell survival is not clear. In this report, we provide evidence that another eIF2AK, the amino acid starvation-dependent general control of amino acid biosynthesis kinase (GCN2), is also involved in hypoxia-induced eIF2alpha phosphorylation. We demonstrate that both GCN2 and PERK mediate the cell adaptation to hypoxic stress. High levels of eIF2alpha phosphorylation lead to G(1) arrest and protect cells from hypoxia-induced apoptosis. Reduced phosphorylation of eIF2alpha by knocking out either PERK or GCN2 suppresses hypoxia-induced G(1) arrest and promotes apoptosis in accompany with activation of p53 signal cascade. However, totally abolishing phosphorylation of eIF2alpha inhibits G(1) arrest without promoting apoptosis. On the basis of our results, we propose that the levels of eIF2alpha phosphorylation serve as a "switch" in regulation of G(1) arrest or apoptosis under hypoxic conditions.
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17 MeSH Terms
Genetic podocyte lineage reveals progressive podocytopenia with parietal cell hyperplasia in a murine model of cellular/collapsing focal segmental glomerulosclerosis.
Suzuki T, Matsusaka T, Nakayama M, Asano T, Watanabe T, Ichikawa I, Nagata M
(2009) Am J Pathol 174: 1675-82
MeSH Terms: Animals, Apoptosis, Cell Lineage, Cyclin-Dependent Kinase Inhibitor p21, Disease Models, Animal, Glomerular Filtration Rate, Glomerulosclerosis, Focal Segmental, Hyperplasia, In Situ Nick-End Labeling, Integrases, Ki-67 Antigen, Kidney Glomerulus, Male, Membrane Proteins, Mice, Mice, Knockout, Podocytes, Proteinuria, WT1 Proteins
Show Abstract · Added January 25, 2012
Focal segmental glomerulosclerosis (FSGS) is a progressive renal disease, and the glomerular visceral cell hyperplasia typically observed in cellular/collapsing FSGS is an important pathological factor in disease progression. However, the cellular features that promote FSGS currently remain obscure. To determine both the origin and phenotypic alterations in hyperplastic cells in cellular/collapsing FSGS, the present study used a previously described FSGS model in p21-deficient mice with visceral cell hyperplasia and identified the podocyte lineage by genetic tagging. The p21-deficient mice with nephropathy showed significantly higher urinary protein levels, extracapillary hyperplastic indices on day 5, and glomerular sclerosis indices on day 14 than wild-type controls. X-gal staining and immunohistochemistry for podocyte and parietal epithelial cell (PEC) markers revealed progressive podocytopenia with capillary collapse accompanied by PEC hyperplasia leading to FSGS. In our investigation, non-tagged cells expressed neither WT1 nor nestin. Ki-67, a proliferation marker, was rarely associated with podocytes but was expressed at high levels in PECs. Both terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and electron microscopy failed to show evidence of significant podocyte apoptosis on days 5 and 14. These findings suggest that extensive podocyte loss and simultaneous PEC hyperplasia is an actual pathology that may contribute to the progression of cellular/collapsing FSGS in this mouse model. Additionally, this is the first study to demonstrate the regulatory role of p21 in the PEC cell cycle.
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19 MeSH Terms
Thiazolidinediones regulate expression of cell cycle proteins in human prostate cancer cells via PPARgamma-dependent and PPARgamma-independent pathways.
Lyles BE, Akinyeke TO, Moss PE, Stewart LV
(2009) Cell Cycle 8: 268-77
MeSH Terms: Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation, Cyclin D1, Cyclin-Dependent Kinase Inhibitor p21, Humans, Male, PPAR gamma, Prostatic Neoplasms, RNA, Small Interfering, Rosiglitazone, Signal Transduction, Thiazolidinediones
Show Abstract · Added March 27, 2014
Thiazolidinediones (TZDs) are peroxisome proliferator activated receptor gamma (PPARgamma) ligands that have been reported to reduce proliferation of human prostate cancer cells. However, the mechanisms by which TZDs inhibit prostate cancer cell proliferation are not fully understood. In addition, it is not known if the anti-proliferative effects of TZDs require activation of PPARgamma or are mediated by PPARgamma-independent pathways. The goals of this study were to assess whether TZDs regulate expression of proteins that control the transition from G1 to S phase of the cell cycle and define the role of PPARgamma in these TZD-induced responses in androgen-independent human prostate cancer cell lines. Western blot analysis revealed that growth inhibitory concentrations of the TZDs rosiglitazone and ciglitazone induced expression of the cyclin dependent kinase inhibitor p21 and decreased cyclin D1 levels in the androgen independent PC-3 cell line. Phosphorylation of retinoblastoma protein at Serine 780 was also reduced in PC-3 cells exposed to ciglitazone. Furthermore, growth inhibitory concentrations of ciglitazone increased p21 and lowered cyclin D1 expression within C4-2 cells. PPARgamma-directed siRNAs inhibited the ability of rosiglitazone to regulate expression of cyclin D1 and p21. However, knockdown of PPARgamma did not significantly reduce ciglitazone-induced alterations in cyclin D1 and p21. Furthermore PPARgamma siRNA did not prevent inhibition of PC-3 cell proliferation by either TZD. Thus, activation of PPARgamma is involved in rosiglitazone-induced alterations in cell cycle protein expression. However, the alterations in protein expression and proliferation induced by ciglitazone occur primarily via PPARgamma-independent signaling pathways.
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13 MeSH Terms
Cyclin-dependent kinase inhibitor, p21WAF1/CIP1, is involved in adipocyte differentiation and hypertrophy, linking to obesity, and insulin resistance.
Inoue N, Yahagi N, Yamamoto T, Ishikawa M, Watanabe K, Matsuzaka T, Nakagawa Y, Takeuchi Y, Kobayashi K, Takahashi A, Suzuki H, Hasty AH, Toyoshima H, Yamada N, Shimano H
(2008) J Biol Chem 283: 21220-9
MeSH Terms: 3T3 Cells, Adipocytes, Animals, Apoptosis, Cell Differentiation, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Hypertrophy, Insulin Resistance, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Obesity, Tumor Suppressor Protein p53
Show Abstract · Added March 27, 2013
Both adipocyte hyperplasia and hypertrophy are determinant factors for adipocyte differentiation during the development of obesity. p21(WAF1/CIP1), a cyclin-dependent kinase inhibitor, is induced during adipocyte differentiation; however, its precise contribution to this process is unknown. Using both in vitro and in vivo systems, we show that p21 is crucial for maintaining adipocyte hypertrophy and obesity-induced insulin resistance. The absence of p21 in 3T3-L1 fibroblasts by RNA-mediated interference knockdown or in embryonic fibroblasts from p21(-/-) mice impaired adipocyte differentiation, resulting in smaller adipocytes. Despite normal adipose tissue mass on a normal diet, p21(-/-) mice fed high energy diets had reduced adipose tissue mass and adipocyte size accompanied by a marked improvement in insulin sensitivity. Knockdown of p21 in enlarged epididymal fat of diet-induced obese mice and also in fully differentiated 3T3-L1 adipocytes caused vigorous apoptosis by activating p53. Thus, p21 is involved in both adipocyte differentiation and in protecting hypertrophied adipocytes against apoptosis. Via both of these mechanisms, p21 promotes adipose tissue expansion during high fat diet feeding, leading to increased downstream pathophysiological consequences such as insulin resistance.
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15 MeSH Terms
Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells.
Murata-Kamiya N, Kurashima Y, Teishikata Y, Yamahashi Y, Saito Y, Higashi H, Aburatani H, Akiyama T, Peek RM, Azuma T, Hatakeyama M
(2007) Oncogene 26: 4617-26
MeSH Terms: Adenocarcinoma, Antigens, Bacterial, Bacterial Proteins, Cadherins, Cell Line, Cell Nucleus, Cell Transformation, Neoplastic, Cyclin-Dependent Kinase Inhibitor p21, Cytoplasm, Gastric Mucosa, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Intestinal Mucosa, Mucin-2, Mucins, Phosphorylation, Precancerous Conditions, Stomach Neoplasms, Transcriptional Activation, Tyrosine, beta Catenin
Show Abstract · Added March 5, 2014
Infection with Helicobacter pylori cagA-positive strains is associated with gastric adenocarcinoma. Intestinal metaplasia is a precancerous lesion of the stomach characterized by transdifferentiation of the gastric mucosa to an intestinal phenotype. The H. pylori cagA gene product, CagA, is delivered into gastric epithelial cells, where it undergoes tyrosine phosphorylation by Src family kinases. Tyrosine-phosphorylated CagA specifically binds to and activates SHP-2 phosphatase, thereby inducing cell-morphological transformation. We report here that CagA physically interacts with E-cadherin independently of CagA tyrosine phosphorylation. The CagA/E-cadherin interaction impairs the complex formation between E-cadherin and beta-catenin, causing cytoplasmic and nuclear accumulation of beta-catenin. CagA-deregulated beta-catenin then transactivates beta-catenin-dependent genes such as cdx1, which encodes intestinal specific CDX1 transcription factor. In addition to beta-catenin signal, CagA also transactivates p21(WAF1/Cip1), again, in a phosphorylation-independent manner. Consequently, CagA induces aberrant expression of an intestinal-differentiation marker, goblet-cell mucin MUC2, in gastric epithelial cells that have been arrested in G1 by p21(WAF1/Cip1). These results indicate that perturbation of the E-cadherin/beta-catenin complex by H. pylori CagA plays an important role in the development of intestinal metaplasia, a premalignant transdifferentiation of gastric epithelial cells from which intestinal-type gastric adenocarcinoma arises.
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22 MeSH Terms
Oncogenic function of a novel WD-domain protein, STRAP, in human carcinogenesis.
Halder SK, Anumanthan G, Maddula R, Mann J, Chytil A, Gonzalez AL, Washington MK, Moses HL, Beauchamp RD, Datta PK
(2006) Cancer Res 66: 6156-66
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, COS Cells, Cell Transformation, Neoplastic, Chlorocebus aethiops, Colorectal Neoplasms, Cyclin-Dependent Kinase Inhibitor p21, Enzyme Activation, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, MAP Kinase Signaling System, Mice, Mink, Mitogen-Activated Protein Kinase Kinases, NIH 3T3 Cells, Neoplasm Proteins, Oncogenes, Phosphorylation, Proteins, Retinoblastoma Protein, Transforming Growth Factor beta
Show Abstract · Added February 17, 2014
The development and progression of malignancies is a complex multistage process that involves the contribution of a number of genes giving growth advantage to cells when transformed. The role of transforming growth factor-beta (TGF-beta) in carcinogenesis is complex with tumor-suppressor or prooncogenic activities depending on the cell type and the stage of the disease. We have previously reported the identification of a novel WD-domain protein, STRAP, that associates with both TGF-beta receptors and that synergizes with the inhibitory Smad, Smad7, in the negative regulation of TGF-beta-induced transcription. Here, we show that STRAP is ubiquitously expressed and is localized in both cytoplasm and nucleus. STRAP is up-regulated in 60% colon and in 78% lung carcinomas. Stable expression of STRAP results in activation of mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and in down-regulation of the cyclin-dependent kinase inhibitor p21(Cip1), which results in retinoblastoma protein hyperphosphorylation. In addition, we have observed that Smad2/3 phosphorylation, TGF-beta-mediated transcription, and growth inhibition are induced in STRAP-knockout mouse embryonic fibroblasts compared with wild-type cells. Ectopic expression of STRAP in A549 lung adenocarcinoma cell line inhibits TGF-beta-induced growth inhibition and enhances anchorage-independent growth of these cells. Moreover, overexpression of STRAP increases tumorigenicity in athymic nude mice. Knockdown of endogenous STRAP by small interfering RNA increases TGF-beta signaling, reduces ERK activity, increases p21(Cip1) expression, and decreases tumorigenicity. Taken together, these results suggest that up-regulation of STRAP in human cancers may provide growth advantage to tumor cells via TGF-beta-dependent and TGF-beta-independent mechanisms, thus demonstrating the oncogenic function of STRAP.
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22 MeSH Terms
Restoration of TGF-beta signalling reduces tumorigenicity in human lung cancer cells.
Anumanthan G, Halder SK, Osada H, Takahashi T, Massion PP, Carbone DP, Datta PK
(2005) Br J Cancer 93: 1157-67
MeSH Terms: Animals, Apoptosis, Carcinoma, Non-Small-Cell Lung, Cell Proliferation, Cell Transformation, Neoplastic, Cyclin-Dependent Kinase Inhibitor p21, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Nude, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Signal Transduction, Smad Proteins, Transcriptional Activation, Transforming Growth Factor beta, Tumor Cells, Cultured, Xenograft Model Antitumor Assays
Show Abstract · Added March 5, 2014
Members of the transforming growth factor-beta (TGF-beta) family regulate a wide range of biological processes including cell proliferation, migration, differentiation, apoptosis, and extracellular matrix deposition. Resistance to TGF-beta-mediated tumour suppressor function in human lung cancer may occur through the loss of type II receptor (TbetaRII) expression. In this study, we investigated the expression pattern of TbetaRII in human lung cancer tissues by RT-PCR and Western blot analyses. We observed downregulation of TbetaRII in 30 out of 46 NSCLC samples (65%) by semiquantitative RT-PCR. Western blot analyses with tumour lysates showed reduced expression of TbetaRII in 77% cases. We also determined the effect of TbetaRII expression in lung adenocarcinoma cell line (VMRC-LCD) that is not responsive to TGF-beta due to lack of TbetaRII expression. Stable expression of TbetaRII in these cells restored TGF-beta-mediated effects including Smad2/3 and Smad4 complex formation, TGF-beta-responsive reporter gene activation, inhibition of cell proliferation and increased apoptosis. Clones expressing TbetaRII showed reduced colony formation in soft-agarose assay and significantly reduced tumorigenicity in athymic nude mice. Therefore, these results suggest that reestablishment of TGF-beta signalling in TbetaRII null cells by stable expression of TbetaRII can reverse malignant behaviour of cells and loss of TbetaRII expression may be involved in lung tumour progression.
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20 MeSH Terms
Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants.
Hemann MT, Bric A, Teruya-Feldstein J, Herbst A, Nilsson JA, Cordon-Cardo C, Cleveland JL, Tansey WP, Lowe SW
(2005) Nature 436: 807-11
MeSH Terms: Adoptive Transfer, Alleles, Animals, Apoptosis, Apoptosis Regulatory Proteins, Bcl-2-Like Protein 11, Burkitt Lymphoma, Carrier Proteins, Cell Cycle Proteins, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p21, Genes, myc, Humans, Membrane Proteins, Mice, Mice, Inbred C57BL, Mutation, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-myc, Stem Cell Transplantation, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53
Show Abstract · Added March 10, 2014
The c-Myc oncoprotein promotes proliferation and apoptosis, such that mutations that disable apoptotic programmes often cooperate with MYC during tumorigenesis. Here we report that two common mutant MYC alleles derived from human Burkitt's lymphoma uncouple proliferation from apoptosis and, as a result, are more effective than wild-type MYC at promoting B cell lymphomagenesis in mice. Mutant MYC proteins retain their ability to stimulate proliferation and activate p53, but are defective at promoting apoptosis due to a failure to induce the BH3-only protein Bim (a member of the B cell lymphoma 2 (Bcl2) family) and effectively inhibit Bcl2. Disruption of apoptosis through enforced expression of Bcl2, or loss of either Bim or p53 function, enables wild-type MYC to produce lymphomas as efficiently as mutant MYC. These data show how parallel apoptotic pathways act together to suppress MYC-induced transformation, and how mutant MYC proteins, by selectively disabling a p53-independent pathway, enable tumour cells to evade p53 action during lymphomagenesis.
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24 MeSH Terms
Murine double minute 2 as a therapeutic target for radiation sensitization of lung cancer.
Cao C, Shinohara ET, Niermann KJ, Donnelly EF, Chen X, Hallahan DE, Lu B
(2005) Mol Cancer Ther 4: 1137-45
MeSH Terms: Animals, Apoptosis, Cell Cycle Proteins, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p21, Endothelium, Vascular, Humans, Lung Neoplasms, Mice, Nuclear Proteins, Oligonucleotides, Antisense, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Radiation-Sensitizing Agents, Transfection, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Umbilical Cord, Up-Regulation
Show Abstract · Added February 28, 2014
Murine double minute 2 (MDM2) inhibits p53-mediated functions, which are essential for therapies using DNA-damaging agents. The purpose of this study was to determine whether MDM2 inhibition enhances the radiosensitivity of a lung cancer model. The effects of MDM2 inhibition on tumor vasculature were also studied. Transient transfection of H460 lung cancer cells and human umbilical vascular endothelial cells (HUVEC) with antisense oligonucleotides (ASODN) against MDM2 resulted in a reduced level of MDM2 and increased levels of p21 and p53. Clonogenic assays showed that inhibition of MDM2 greatly decreased cell survival following irradiation. Quantification of apoptotic cells by 7-aminoactinomycin D staining and of senescent cells by X-gal staining showed that both processes were significantly increased in H460 cells treated with MDM2-specific ASODN and radiation. H460 xenografts that were treated with MDM2 ASODN plus radiotherapy also showed significant growth delay (P < 0.001) and increased apoptosis by terminal deoxynucleotidyl transferase-mediated nick end labeling staining. HUVECs transfected with MDM2-specific ASODN showed impaired viability and migration with decreased tube formation. Doppler studies showed that tumor blood flow was compromised when H460 xenografts were treated with MDM2-specific ASODN and radiation. A combination of radiotherapy and inhibition of MDM2 through the antisense approach results in improved tumor control in the H460 lung cancer model. This implies that a similar strategy should be investigated among patients with locally advanced lung cancer, receiving thoracic radiotherapy.
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19 MeSH Terms