scholarly journals High Mobility Group A1 Chromatin Regulators Function As Critical Drivers of Leukemogenesis in Preclinical Models of Relapsed, Pediatric B-Cell ALL

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3946-3946
Author(s):  
Liping Li ◽  
Katharina Hayer ◽  
Lingling Xian ◽  
Li Luo ◽  
Leslie Cope ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
High Mobility ◽  
Transcriptional Networks ◽  
Rna Seq ◽  
Cycle Progression ◽  
Short Hairpin ◽  
Reh Cells

Introduction: Acute B-cell lymphoblastic leukemia (B-ALL) is the most common form of childhood leukemia and the leading cause of death in children with cancer. While therapy is often curative, about 10-15% of children will relapse with recurrent disease and abysmal outcomes. Actionable mechanisms that mediate relapse remain largely unknown. The gene encoding the High Mobility Group A1(HMGA1) chromatin regulator is overexpressed in diverse malignancies where high levels portend poor outcomes. In murine models, we discovered thatHmga1 overexpression is sufficient for clonal expansion and progression to aggressive acute lymphoid leukemia (Cancer Res 2008,68:10121, 2018,78:1890; Nature Comm 2017,8:15008). Further, HMGA1 is overexpressed in pediatric B-ALL (pB-ALL) blasts with highest levels in children who relapse early compared to those who achieve chronic remissions. Together, these findings suggest that HMGA1 is required for leukemogenesis and may foster relapse in B-ALL. We therefore sought to: 1) test the hypothesis that HMGA1 is a key epigenetic regulator required for leukemogenesis and relapse in pB-ALL, and, 2) elucidate targetable mechanisms mediated by HMGA1 in leukemogenesis. Methods: We silenced HMGA1 via lentiviral delivery of short hairpin RNAs targeting 2 different sequences in cell lines derived from relapsed pB-ALL (REH, 697). REH cells harbor the TEL-AML1 fusion; 697 cells express BCL2, BCL3, and cMYC. Next, we assessed leukemogenic phenotypes in vitro (proliferation, cell cycle progression, apoptosis, and clonogenicity) and leukemogenesis invivo. To dissect molecular mechanisms underlying HMGA1, we performed RNA-Seq and applied in silico pathway analysis. Results: There is abundant HMGA1 mRNA and protein in both pB-ALL cell lines and HMGA1 was effectively silenced by short hairpin RNA. Further, silencing HMGA1 dramatically halts proliferation in both cell lines, leading to a decrease in cells in S phase with a concurrent increase in G0/S1. Apoptosis also increased by 5-10% after HMGA1 silencing based on flow cytometry for Annexin V. In colony forming assays, silencing HMGA1 impaired clonogenicity in both pB-ALL cell lines. To assess HMGA1 function in leukemogenesis in vivo, we implanted control pB-ALL cells (transduced with control lentivirus) or those with HMGA1 silencing via tail vein injection into immunosuppressed mice (NOD/SCID/IL2 receptor γ). All mice receiving control REH cells succumbed to leukemia with a median survival of only 29 days. At the time of death, mice had marked splenomegaly along with leukemic cells circulating in the peripheral blood and infiltrating both the spleen and bone marrow. In contrast, mice injected with REH cells with HMGA1 silencing survived for >40 days (P<0.001) and had a significant decrease in tumor burden in the peripheral blood, spleen, and bone marrow. Similar results were obtained with 697 cells, although this model was more fulminant with control mice surviving for a median of only 17 days. To determine whether the leukemic blasts found in mice injected with ALL cells after HMGA1 silencing represented a clone that expanded because it escaped HMGA1 silencing, we assessed HMGA1 levels and found that cells capable of establishing leukemia had high HMGA1 expression, with levels similar to those observed in control cells without HMGA1 silencing. RNA-Seq analyses from REH and 697 cell lines with and without HMGA1 silencing revealed that HMGA1 up-regulates transcriptional networks involved in RAS/MAPK/ERK signaling while repressing the IDH1 metabolic gene, the latter of which functions in DNA and histone methylation. Studies are currently underway to identify effective agents to target HMGA1 pathways. Conclusions: Silencing HMGA1 dramatically disrupts leukemogenic phenotypes in vitro and prevents the development of leukemia in mice. Mechanistically, RNA-Seq analyses revealed that HMGA amplifies transcriptional networks involved cell cycle progression and epigenetic modifications. Our findings highlight the critical role for HMGA1 as a molecular switch required for leukemic transformation in pB-ALL and a rational therapeutic target that may be particularly relevant for relapsed B-ALL. Disclosures No relevant conflicts of interest to declare.

scholarly journals High Mobility Group A1 Chromatin Regulators: Key Epigenetic Switches and Therapeutic Targets Required for Leukemic Transformation in JAK2 Mutant MPN

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1680-1680
Author(s):  
Liping Li ◽  
Wenyan Lu ◽  
Alison R. Moliterno ◽  
Lingling Xian ◽  
Joseph Kim ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
High Mobility ◽  
Transcriptional Networks ◽  
Murine Models ◽  
Rna Seq ◽  
Leukemic Transformation ◽  
Cycle Progression ◽  
Cd34 Cells

Introduction: Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell (HSC) disorders characterized by hyperactive JAK/STAT signaling and increased risk of transformation to myelofibrosis (MF) and acute myeloid leukemia (AML). However, mechanisms driving progression remain elusive and therapies are ineffective after leukemia develops. The High Mobility Group A1/2 (HMGA1/2) genes encode oncogenic chromatin remodeling proteins which are overexpressed in aggressive solid tumors where they portend adverse outcomes. HMGA1/2 genes are also up-regulated in hematologic malignancies and MPN with disease progression. In murine models, Hmga1/2 overexpression drives clonal expansion and deregulated proliferation while Hmga1 overexpression is sufficient for lymphoid leukemic transformation. We therefore sought to: 1) test the hypothesis that HMGA1/2 proteins are rational therapeutic targets required for leukemic transformation in MPN, 2) elucidate mechanisms mediated by HMGA1/2 during disease progression, and, 3) identify therapeutic approaches to disrupt HMGA function and intercept the transition from chronic disease to aggressive leukemia. Methods: We compared HMGA1/2 in JAK2V617F mutant AML cell lines from MPN patients (DAMI, SET-2), CD34+ cells from PV patients during chronic and transformation phases, and JAK2V617F murine models of PV (transgenic JAK2V617F) and PV-AML (transgenic JAK2V617F/MPLSV). To elucidate HMGA1/2 function, we silenced HMGA1 or HMGA2 via short hairpin RNA in human MPN-AML cells and generated murine models of PV-AML with heterozygous Hmga1 or Hmga2 deficiency. To dissect molecular mechanisms underlying HMGA, we compared RNA-Seq from MPN-AML cell lines after gene silencing. Finally, to identify therapies to target HMGA pathways, we integrated the RNA-Seq data with the Broad Connectivity Map (cMAP). Results: There is a marked up-regulation in HMGA1/2 in CD34+ cells from PV patients after transformation to AML and in leukemic blasts from our PV-AML mouse model. Conversely, silencing HMGA1 or HMGA2 in human MPN-AML cell lines (DAMI, SET-2) dramatically halts proliferation, disrupts clonogenicity, and prevents leukemia development in mice. Further, heterozygous Hmga1 deficiency prolongs survival in the transgenic PV-AML murine model with fulminant leukemia and early mortality, although Hmga2 deficiency has no effect. RNA-Seq analyses from human MPN-AML cell lines revealed that HMGA1 up-regulates transcriptional networks involved in cell cycle progressions (E2F targets, mitotic spindle, G2M checkpoint, MYC targets) while repressing immune pathways (inflammation, interferon gamma) and oxidative phosphorylation. HMGA2 up-regulates similar pathways, but represses TNFalpha signaling. cMAP identified inhibitors of histone deacetylation and cell cycle progression as potential agents to target HMGA1 pathways; DNA synthesis inhibitors were predicted to target HMGA2 pathways. Cytotoxicity assays demonstrate that epigenetic therapy with HDAC inhibitors synergizes with Ruxolitinib in JAK2 mutant MPN cells after transformation to leukemia. Conclusions: HMGA1/2 genes are overexpressed in MPN with highest levels after leukemic transformation. Further, silencing HMGA1/2 disrupts leukemogenic phenotypes in vitro and prevents the development of leukemia in mice. In addition, heterozygous deficiency of Hmga1 prolongs survival in a fulminant MPN-AML model. Mechanistically, RNA-Seq analyses revealed that HMGA amplifies transcriptional networks involved cell cycle progression, which can be targeted with epigenetic therapies. Our findings further underscore the key role for HMGA as an epigenetic switch required for leukemic transformation in MPN and opens the door to novel therapeutic approaches to intercept the transition from chronic indolent disease to aggressive leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Anticancer Activity of Cynomorium coccineum

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 354 ◽  
Author(s):  
Mouna Sdiri ◽  
Xiangmin Li ◽  
William Du ◽  
Safia El-Bok ◽  
Yi-Zhen Xie ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Cycle Progression ◽  
Cycle Progression

The extensive applications of Cynomorium species and their rich bioactive secondary metabolites have inspired many pharmacological investigations. Previous research has been conducted to examine the biological activities and numerous interesting pharmaceutical activities have been reported. However, the antitumor activities of these species are unclear. To understand the potential anticancer activity, we screened Cynomorium coccineum and Cynomorium songaricum using three different extracts of each species. In this study, the selected extracts were evaluated for their ability to decrease survival rates of five different cancer cell lines. We compared the cytotoxicity of the three different extracts to the anticancer drug vinblastine and one of the most well-known medicinal mushrooms Amaurederma rude. We found that the water and alcohol extracts of C. coccineum at the very low concentrations possessed very high capacity in decreasing the cancer cells viability with a potential inhibition of tumorigenesis. Based on these primitive data, we subsequently tested the ethanol and the water extracts of C. coccineum, respectively in in vitro and in vivo assays. Cell cycle progression and induction of programmed cell death were investigated at both biological and molecular levels to understand the mechanism of the antitumor inhibitory action of the C. coccineum. The in vitro experiments showed that the treated cancer cells formed fewer and smaller colonies than the untreated cells. Cell cycle progression was inhibited, and the ethanol extract of C. coccineum at a low concentration induced accumulation of cells in the G1 phase. We also found that the C. coccineum’s extracts suppressed viability of two murine cancer cell lines. In the in vivo experiments, we injected mice with murine cancer cell line B16, followed by peritoneal injection of the water extract. The treatment prolonged mouse survival significantly. The tumors grew at a slower rate than the control. Down-regulation of c-myc expression appeared to be associated with these effects. Further investigation showed that treatment with C. coccineum induced the overexpression of the tumor suppressor Foxo3 and other molecules involved in inducing autophagy. These results showed that the C. coccineum extract exerts its antiproliferative activity through the induction of cell death pathway. Thus, the Cynomorium plants appear to be a promising source of new antineoplastic compounds.

Centrosome Aberrations, Disturbed Mitotic Spindle Formation and G1 Arrest in Normal and Leukemic Cells Treated with the SRC/ABL Inhibitor Dasatinib.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2167-2167
Author(s):  
Alice Fabarius ◽  
Michelle Giehl ◽  
Alwin Kraemer ◽  
Oliver Frank ◽  
Martin C. Mueller ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Mitotic Spindle ◽  
Cell Cycle Progression ◽  
Dermal Fibroblasts ◽  
G1 Arrest ◽  
Osteosarcoma Cell ◽  
Cycle Progression ◽  
Spindle Formation

Abstract Multitargeted ABL inhibitors have been developed to simultaneously inhibit various pathways associated with proliferation in BCR-ABL+ diseases. Dasatinib (Bristol Myers Squibb) is a potent inhibitor targeting ABL, SRC, and other tyrosine kinases. SRC kinases are required for progression through the initial phase of mitosis. Centrosomes play a fundamental role in mitotic spindle organization, chromosome segregation and genetic stability. We sought to evaluate the activity of dasatinib on proliferation, centrosome status, spindle formation, and cell cycle progression in vitro and in vivo. Normal human dermal fibroblasts (NHDF), Chinese hamster embryonal fibroblasts (CHE), and the human osteosarcoma cell line U2OS were treated with serial concentrations (1nM-10μM) of dasatinib for 3 weeks. Effects of dasatinib were compared with data achieved with the ABL inhibitors imatinib (Novartis, 5–20μM) and nilotinib (Novartis, 0.5–20μM), the specific SRC inhibitor PP2 (Calbiochem-Novabiochem, 0.1–2μM), the ABL/LYN inhibitor INNO-406 (Innovive, 0.1–2μM), and solvent control. Bone marrow and peripheral blood samples from 18 patients (pts, 10 m, 8 f; median age 57 yrs, range 26–75) treated with dasatinib (70mg bid) after imatinib failure for a median of 11 mo (range, 3–16) were investigated. 17 pts had chronic myeloid leukemia (CML) in chronic phase. One patient suffered from a gastrointestinal stromal tumor. For comparison, 3 untreated CML pts and 3 healthy individuals were evaluated. Cell proliferation was determined in liquid culture incubated with serial dilutions of the inhibitor. Centrosome morphology and spindle formation were evaluated after pericentrin and α-tubulin staining, respectively. Cell cycle progression was analyzed by FACS and expression of EG5 by immunofluorescence microscopy. Dasatinib induced a G1 cell cycle arrest in all cell lines tested and in pts associated with a shift to 1n DNA ploidy and absence of EG5 as a marker for G2 phase/mitosis. In vitro, centrosomal aberrations and delay of spindle formation were observed in a dose dependent fashion. In pts, centrosome alterations were found in a median of 17% (range, 10–15) of cells. Disturbed spindle formation was observed in 9/18 pts. In comparison, incubation with imatinib and nilotinib was associated with centrosome aberrations but not with defects of spindle formation and G1 arrest. PP2 induced S-phase arrest; centrosome aberrations were observed at higher dosages (1–2 μM) only, spindle formation was not affected. INNO-406 was associated with both centrosome aberrations and disturbed spindle formation. In pharmacological doses, proliferation of BCR-ABL neg. cell lines was inhibited after dasatinib treatment, but not after incubation with imatinib, nilotinib, PP2, or INNO-406. In conclusion, dasatinib blocks the G1/S transition and thereby inhibits cell growth in normal and neoplastic cells. In addition, it induces both centrosomal and spindle aberrations. Effects of dasatinib are not based on SRC inhibition alone but may be associated with the combination of SRC and ABL inhibition or with non-specific effects on multiple kinases. Therefore, dasatinib should be defined as a cytostatic drug with a strong targeted component resulting in a preferential inhibition of cells harboring a specific target, like BCR-ABL.

Potent cytotoxicity and inhibition of pan-cell cycle progression by Alchemix, a novel alkylating anthraquinone

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12030-12030
Author(s):  
A. A. Epenetos ◽  
K. Pors ◽  
P. J. Smith ◽  
L. H. Patterson
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Topoisomerase Ii ◽  
Human Tumors ◽  
Drug Resistant ◽  
Cycle Progression ◽  
Topo Ii

12030 Introduction: DNA topoisomerase II (topo II) is crucial to the maintenance of cancer cells in a proliferative state. DNA intercalation is a crucial part of topo II inhibition by DNA affinic anthraquinones. Potent cytotoxicity of anthraquinones, is related to their slow rate of dissociation from DNA, the kinetics of which favours long-term trapping of the topo-DNA complexes. Currently available DNA interacting agents at best promote a transient inhibition of topo II, since the topo-drug-DNA ternary complex is reversed by removal of the intracellular drug pool. Results: Alchemix cell cycle events: DNA content and Cyclin B1 expression were measured using flow cytometry and a p53 functional human osteosarcoma cell line (U2-OS) The results indicate: (ii) slow pan-cell cycle progression and mitotic commitment with a limited expression of G2 arrest, (iii) B1 cyclin tracking reveals that escape from Alchemix-induced cell cycle arrest in G2 is forcing some cells to enter polyploidy via an aberrant mitosis in keeping with topoisomerase II inhibition. Alchemix in vitro activity against the NCI human cell line panel including several drug resistant cancer cell lines had a mean IG50 = 49 nM. 11 of the 24 cell lines tested have an IG50 of <10 nM. Alchemix retains potent activity against chemotherapy resistant tumors including drug resistant ones. Conclusions: Alchemix possesses potent activity across a variety of different human tumors and significantly shows potent activity in cisplatin and anthracyline resistant human tumors Alchemix has pan-cell cycle effects. Multilevel targeting by Alchemix reduces the probability of evasion of cell cycle related pharmacodynamic responses. Results help explain the activity of Alchemix in both cisplatin and anthracycline resistant tumors in vitro and in vivo. [Table: see text]

The F-Box Protein Skp2 Regulates Expression of p27 in BCR-ABL Transformed Cell Lines and Is Required for Induction of Myeloproliferative Disease in a Murine Model.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 742-742
Author(s):  
Anupriya Agarwal ◽  
Thomas G.P. Bumm ◽  
Amie Corbin ◽  
Thomas O’Hare ◽  
Marc Loriaux ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Dependent Manner ◽  
Myeloproliferative Disease ◽  
Cycle Progression ◽  
Cell Counts ◽  
F Box Protein ◽  
Transformed Cell Lines

Abstract Background:The cyclin-dependent kinase inhibitor p27 is a central regulator of cell cycle progression, whose function is perturbed in many human cancers, either due to decreased expression or abnormal localization. p27 levels are negatively correlated with Skp2, the F-box protein of SCFSKP2, a E3 ubiquitin ligase targeting nuclear p27 for degradation. Skp2 has been shown to cooperate with mutant Ras in in vitro transformation assays, implicating Skp2 as a bona fide oncogene. In chronic myeloid leukemia cell lines, p27 is down-regulated in a Bcr-Abl dependent fashion, while cytoplasmic accumulation has been described in primary CML cells. We herefore hypothesized that Bcr-Abl may regulate p27 via Skp2. Experimental approach and results:Mo7e-p210BCR-ABL treated with 2.5 μM imatinib arrested in G0/G1 in a time-dependent manner (53.6±2, 58.3±2, 71.9±1% at 4, 8 and 16h), correlated with reduced in vitro kinase activity of Cdk2 (32% of controls at 16h). Western blot analysis showed a marginal increase of cytoplasmic p27 and 2.5-fold accumulation of nuclear p27 that preceded G0/1 arrest. Despite the reduced Cdk2 activity, most p27 was phosphorylated on T187, a target of cdk2/cyclinE, suggesting reduced degradation of phospo-p27 (T187). Degradation of nuclear p27 is mediated by SCFSKP2 and degradation of cytoplasmic p27 by the recently discovered KPC complex. We therefore assayed expression SCFSKP2 components and KPC1/2 by immunoblot analysis of imatinib-treated cells. Skp2 expression was greatly reduced compared to controls while expression of other SCFSKP2 components and KPC1/2 was unchanged, consistent with up-regulation of nuclear but not cytoplasmic p27 and suggesting a central role of Skp2 in mediating p27 degradation in Bcr-Abl positive cells. To test whether Skp2 is crucial for Bcr-Abl-driven leukemogenesis, we infected bone marrow of Skp2+/+ and Skp2−/− mice with BCR-ABL retrovirus. No consistent difference was observed in B-cell transformation assay (Whitlock-Witte cultures). However, formation of myeloid colonies in semisolid media was reduced in Skp2−/− compared to Skp2+/+ marrow [46.4±10% of controls (p=0.002) without and 76.6±9% of controls (p=0.008) with cytokines, n=6]. Skp2+/+ mice transplanted with BCR-ABL infected Skp2−/− marrow had significantly longer median survival (19days, range 12–60days, n=8) compared to recipients of Skp2+/+ marrow (13days, range 12–22days, n=10) (p=0.0034) with significant reduction of spleen weight (0.42±0.07g vs. 0.28±0.09g, p=0.004) and white blood cell counts (median 59x103/μl, range 9.6–142x103/μl, vs. 7.9x103/μl, range 0.8–87x103/μl, p=0.02). Histology and immunophenotyping of tissues (blood, marrow, spleen) revealed no signinificant differences between Skp2+/+ and Skp2−/− mice. Conclusions: Our data suggest that the primary cell cycle effect of Bcr-Abl kinase is up-regulation of Skp2. This leads to increased activity of SCFSKP2, inducing degradation of T187 phosphorylated p27 which in turn promotes cell cycle progression by relieving suppression of Cdk2. Skp2 is required for Bcr-Abl to fully realize its potential to induce myeloproliferative disease, providing the first in vivo evidence that SKP2 is an oncogene. Targeting Skp2-p27 interactions to prevent p27 degradation may be therapeutically useful in malignancies with a high Skp2/p27 ratio.

Synergistic Anti-Cancer Effects of Arsenic Trioxide and Paclitaxel On Human Malignant Lymphocytes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4809-4809
Author(s):  
Ying-Li Wu ◽  
Xu-Fang Duan ◽  
Han-Zhang Xu ◽  
Guo-Qiang Chen
Keyword(s):  
Cell Cycle ◽  
Arsenic Trioxide ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Conflicts Of Interest ◽  
Combined Treatment ◽  
Human Tumor ◽  
Mitotic Arrest ◽  
Cycle Progression

Abstract Abstract 4809 Arsenic trioxide (ATO), an effective drug in the treatment of acute promyelocytic leukemia (APL), and its combination with other chemotherapeutic drugs have been shown to present some activities in other malignant cells besides APL. Increasing reports showed that ATO produces mitotic arrest possibly through targeting to tubulins before apoptosis induction in human tumor cells. Aberrations in the control of cell cycle progression occur in the majority of human malignancies; hence, tubulins are promising targets for anticancer therapy. Here, we define the cellular effects with ATO, alone or in association with paclitaxel, the first identified microtubules stabilizing agent, with respect to inhibition of cell proliferation and cell cycle progression and induction of apoptosis in malignant lymphocytic cell lines Jurkat, Raji, and NAMALWA as well as fresh acute lymphocytic leukemic (ALL) cells. Our results showed that the co-treatment of ATO and PTX at their lower concentrations could significantly induce mitotic arrest followed by growth inhibition and apoptosis in these cell lines. The combined treatment of ATO with PTX also synergistically decreased the cell viability in primary ALL cells. In vivo and in vitro experiments showed that the combination treatment did not increase the microtubules polymerization compared to ATO or PTX treatment alone. Instead, this synergistic action was attributed to the increase of phosphorylation of cyclin-dependent kinase 1 (Cdk1) on Thr161 and the promotion of the dysregulated activation of Cdk1. Furthermore, we found that the ATO/PTX combination significantly enhanced the activation of spindle checkpoint by inducing the formation of the inhibitory checkpoint complex BubR1/Cdc20. These results provide a rational basis for clinical trials of the combined regimen of ATO and PTX in the treatment of lymphocytic neoplasm. Disclosures: No relevant conflicts of interest to declare.

scholarly journals LMNB2 promotes the progression of colorectal cancer by silencing p21 expression

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Chen-Hua Dong ◽  
Tao Jiang ◽  
Hang Yin ◽  
Hu Song ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Gene Set Enrichment Analysis ◽  
Molecular Therapy ◽  
Cycle Progression ◽  
Cancer Tissues

AbstractColorectal cancer is the second common cause of death worldwide. Lamin B2 (LMNB2) is involved in chromatin remodeling and the rupture and reorganization of nuclear membrane during mitosis, which is necessary for eukaryotic cell proliferation. However, the role of LMNB2 in colorectal cancer (CRC) is poorly understood. This study explored the biological functions of LMNB2 in the progression of colorectal cancer and explored the possible molecular mechanisms. We found that LMNB2 was significantly upregulated in primary colorectal cancer tissues and cell lines, compared with paired non-cancerous tissues and normal colorectal epithelium. The high expression of LMNB2 in colorectal cancer tissues is significantly related to the clinicopathological characteristics of the patients and the shorter overall and disease-free cumulative survival. Functional analysis, including CCK8 cell proliferation test, EdU proliferation test, colony formation analysis, nude mouse xenograft, cell cycle, and apoptosis analysis showed that LMNB2 significantly promotes cell proliferation by promoting cell cycle progression in vivo and in vitro. In addition, gene set enrichment analysis, luciferase report analysis, and CHIP analysis showed that LMNB2 promotes cell proliferation by regulating the p21 promoter, whereas LMNB2 has no effect on cell apoptosis. In summary, these findings not only indicate that LMNB2 promotes the proliferation of colorectal cancer by regulating p21-mediated cell cycle progression, but also suggest the potential value of LMNB2 as a clinical prognostic marker and molecular therapy target.

scholarly journals Interleukin-2 expression in human carcinoma cell lines and its role in cell cycle progression

Oncogene ◽  
2000 ◽  
Vol 19 (4) ◽  
pp. 514-525 ◽  
Author(s):  
Torsten E Reichert ◽  
Shigeki Nagashima ◽  
Yoshiro Kashii ◽  
Joanna Stanson ◽  
Gui Gao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Carcinoma Cell ◽  
Interleukin 2 ◽  
Cycle Progression ◽  
Human Carcinoma ◽  
Carcinoma Cell Lines ◽  
Human Carcinoma Cell

scholarly journals Delayed Cell Cycle Progression and Apoptosis Induced by Hemicellulase-TreatedAgaricus blazei

2007 ◽  
Vol 4 (1) ◽  
pp. 83-94 ◽  
Author(s):  
Masaki Kawamura ◽  
Hirotake Kasai
Keyword(s):  
Cell Cycle ◽  
P38 Mapk ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Combined Treatment ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Activation Effect ◽  
Cycle Progression ◽  
Fraction H

We examined the effects of hemicellulase-treatedAgaricus blazei(AB fraction H, ABH) on growth of several tumor cell lines. ABH inhibited the proliferation of some cell lines without cytotoxic effects. It markedly prolonged the S phase of the cell cycle. ABH also induced mitochondria-mediated apoptosis in different cell lines. However, it had no impact on the growth of other cell lines. ABH induced strong activation of p38 mitogen-activated protein kinase (MAPK) in the cells in which it evoked apoptosis. On the other hand, ABH showed only a weak p38 activation effect in those cell lines in which it delayed cell cycle progression with little induction of apoptosis. However, p38 MAPK-specific inhibitor inhibited both ABH-induced effects, and ABH also caused apoptosis in the latter cells under conditions of high p38 MAPK activity induced by combined treatment with TNF-α. These results indicate that the responsiveness of p38 MAPK to ABH, which differs between cell lines, determines subsequent cellular responses on cell growth.

scholarly journals Molecular cloning of a novel mitogen-inducible nuclear protein with a Ran GTPase-activating domain that affects cell cycle progression.

1995 ◽  
Vol 15 (1) ◽  
pp. 552-560 ◽  
Author(s):  
M Hattori ◽  
N Tsukamoto ◽  
M S Nur-e-Kamal ◽  
B Rubinfeld ◽  
K Iwai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Nuclear Protein ◽  
Interleukin 2 ◽  
Quiescent State ◽  
Cycle Progression ◽  
Ran Gtpase ◽  
G0 Phase ◽  
Nih 3T3

We have cloned a novel cDNA (Spa-1) which is little expressed in the quiescent state but induced in the interleukin 2-stimulated cycling state of an interleukin 2-responsive murine lymphoid cell line by differential hybridization. Spa-1 mRNA (3.5 kb) was induced in normal lymphocytes following various types of mitogenic stimulation. In normal organs it is preferentially expressed in both fetal and adult lymphohematopoietic tissues. A Spa-1-encoded protein of 68 kDa is localized mostly in the nucleus. Its N-terminal domain is highly homologous to a human Rap1 GTPase-activating protein (GAP), and a fusion protein of this domain (SpanN) indeed exhibited GAP activity for Rap1/Rsr1 but not for Ras or Rho in vitro. Unlike the human Rap1 GAP, however, SpanN also exhibited GAP activity for Ran, so far the only known Ras-related GTPase in the nucleus. In the presence of serum, stable Spa-1 cDNA transfectants of NIH 3T3 cells (NIH/Spa-1) hardly overexpressed Spa-1 (p68), and they grew as normally as did the parental cells. When NIH/Spa-1 cells were serum starved to be arrested in the G1/G0 phase of the cell cycle, however, they, unlike the control cells, exhibited progressive Spa-1 p68 accumulation, and following the addition of serum they showed cell death resembling mitotic catastrophes of the S phase during cell cycle progression. The results indicate that the novel nuclear protein Spa-1, with a potentially active Ran GAP domain, severely hampers the mitogen-induced cell cycle progression when abnormally and/or prematurely expressed. Functions of the Spa-1 protein and its regulation are discussed in the context of its possible interaction with the Ran/RCC-1 system, which is involved in the coordinated nuclear functions, including cell division.

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