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  • 1
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    Targeting a lynchpin to treat cancer and autoimmunity
    Springer Science and Business Media LLC ; 2019
    In:  Cell Communication and Signaling Vol. 17, No. 1 ( 2019-12)
    Details
    In: Cell Communication and Signaling, Springer Science and Business Media LLC, Vol. 17, No. 1 ( 2019-12)
    Abstract: Lymphotoxin β receptor (LTβR) plays important roles in the development of the immune system and immune response. At the cellular level, ligand-bound LTβR activates the pro-inflammatory NF-κB pathway but the detailed mechanisms regulating its signaling remain unknown. Understanding them is of high importance since LTβR and its ligands are promising therapeutic targets. Here, we studied the consequences of perturbed cellular cholesterol content on LTβR-induced NF-κB signaling. Methods To modulate cholesterol availability and/or level in lung carcinoma A549 and H2228, and endothelial HUVEC cells different treatment regimens with filipin, methyl-β-cyclodextrin and simvastatin were applied. LTβR localization was studied by confocal microscopy. The activity of LTβR-induced NF-κB pathway was assessed by measuring the levels of NF-κB pathway inhibitor IκBα and phosphorylation of RelA transcription factor by Western blotting. The NF-κB transcriptional response, production of chemokines and adhesion molecules were examined by qRT-PCR, ELISA, and Western blotting, respectively. Adherence of different types of primary immune cells to epithelial A549 cells and endothelial HUVECs was measured fluorometrically. Interactions of LTβR with its protein partners were investigated by immunoprecipitation. Results We showed that filipin-mediated sequestration of cholesterol or its depletion from the plasma membrane with methyl-β-cyclodextrin impaired LTβR internalization and potentiated LTβR-dependent activation of the canonical branch of the NF-κB pathway. The latter was manifested by enhanced degradation of IκBα inhibitor, elevated RelA phosphorylation, substantial increase in the expression of NF-κB target genes encoding, among others, cytokines and adhesion molecules known to play important roles in immune response. It was followed by robust secretion of CXCL8 and upregulation of ICAM1, that favored the adhesion of immune cells (NK and T cells, neutrophils) to A549 cells and HUVECs. Mechanistically, we showed that cholesterol depletion stabilized interactions of ligand-stimulated LTβR with modified forms of TRAF2 and NEMO proteins. Conclusions Our results showed that the reduction of the plasma membrane content of cholesterol or its sequestration strongly potentiated signaling outcome initiated by LTβR. Thus, drugs modulating cholesterol levels could potentially improve efficacy of LTβR-based therapies.
    Type of Medium: Online Resource
    ISSN: 1478-811X
    URL: Article
    URL: Article
    DOI: 10.1186/s12964-019-0460-1
    DOI: 10.21203/rs.2.23782/v1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2126315-2
    SSG: 12
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  • 2
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    Treatment of hippocampal neurons with cyclosporin A results in calcium overload and apoptosis which are independent on NMDA receptor activation : Cyclosporin A affects survival of hippocampal neurons
    Wiley ; 2001
    In:  British Journal of Pharmacology Vol. 133, No. 7 ( 2001-08), p. 997-1004
    Details
    In: British Journal of Pharmacology, Wiley, Vol. 133, No. 7 ( 2001-08), p. 997-1004
    Type of Medium: Online Resource
    ISSN: 0007-1188
    URL: Article
    DOI: 10.1038/sj.bjp.0704177
    Language: English
    Publisher: Wiley
    Publication Date: 2001
    detail.hit.zdb_id: 2029728-2
    SSG: 15,3
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  • 3
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    Inhibition of PIM Kinases in Diffuse Large B-Cell Lymphoma Cells Targets MYC-Dependent Transcriptional Program, Increases CD20 Expression and Augments the Efficacy of Anti-CD20 Antibodies
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 33-34
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 33-34
    Abstract: R-CHOP immunochemotherapy remains standard frontline therapy for newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients. However, this therapy is ineffective in approximately 1/3 of patients, underscoring the need for better treatment modalities. Targeting DLBCL oncogenic drivers is a promising strategy to improve the treatment efficacy and outcome. Although MYC transcription factor is one of the key oncogenes in DLBCL development, direct MYC targeting strategies have been largely ineffective, highlighting the need for other, indirect approaches. For example, MYC expression is stabilized by PIM serine-threonine kinases, indicating that PIM inhibition might be a rational approach to indirectly target MYC. In this study, we assessed the PIM-MYC relationship and the consequences of PIM inhibition in DLBCL. We first evaluated the expression of PIM1-3 and MYC proteins in 57 DLBCL diagnostic sections by immunohistochemistry. In this series, 70.17% of specimens were positive for at least one PIM isoform and 84.22% cases were MYC-positive. 100% of cases with high MYC expression (MYC present in ≥30% of the cells, n=35) were PIM-positive, whereas 86,36% of cases with undetectable or low MYC expression (MYC detected in ≤20% of cells, n= 22) were PIM-negative (Fisher's exact test, p & lt;0.0001). Since the coexpression of MYC and PIMs highlights the functional link between these proteins in DLBCLs, we evaluated the expression of PIM kinases in cell lines following siRNA-mediated MYC knockdown or treatment with MYC-MAX dimerization inhibitor, 10058F4. The genetic or chemical MYC inhibition markedly decreased PIM1-3 expression in six GCB and ABC cell lines. Likewise, knockdown of all three PIM isoforms decreased MYC levels, attenuated proliferation and induced apoptosis. Similarly, PIM blockade with SEL24/MEN1703, a novel pan-PIM/FLT3 inhibitor tested currently in clinical trial in AML patients and exhibiting favorable safety profile, decreased the expression of multiple MYC-dependent genes. To assess the MYC role in PIM inhibitor-mediated toxicity, we generated DHL4 cells expressing degradation-resistant MYC_T58A mutant. MYC_T58A expression partially protected cells from PIM inhibitor-induced proliferation arrest and apoptosis, indicating that the inhibitor's toxicity is at least partially mediated by MYC depletion. The MS4A1 gene, encoding CD20 surface antigen and rituximab target, is regulated by an upstream promoter containing potential MYC-binding sites (E-boxes). MYC association to these regions was confirmed in chromatin immunoprecipitation assays. As expected, in SEL24/MEN1703-treated cells, MYC occupancy at the MS4A1 promoter markedly decreased. To determine the consequences of MYC binding to the MS4A1 promoter, we assessed CD20 levels in a lymphoblastoid cell line carrying tetracycline-regulated (tet-off) MYC. MYC repression markedly elevated transcript and surface CD20 levels in a time-dependent manner, reaching 17.3-fold (transcript) and 3.82-fold (surface) inductions at 96 h. Consistently, the pan-PIM inhibitor decreased MYC expression in DHL4 and RAJI cells and resulted in increased surface CD20 levels up to 3.72-fold of baseline. In cells expressing the MYC_T58A mutant, PIM inhibition did not increase CD20 level, indicating that PIM kinases modulate CD20 surface expression via MYC. Importantly, PIM inhibitors increased CD20 levels also in primary, patient-derived DLBCL cells. These data suggest that indirect MYC targeting via PIM inhibition would lead to increased rituximab activity. Indeed, in PIM inhibitor-treated DHL4 and RAJI cells, rituximab triggered higher complement-dependent toxicity. Likewise, PIM inhibitor potentiated rituximab-dependent uptake of DHL4 and DHL6 cells by human monocyte-derived macrophages in antibody-dependent cellular phagocytosis assay. Taken together, we characterize a PIM-MYC regulatory circuit promoting DLBCL growth and resistance to anti-CD20 antibody. We also demonstrate that PIM inhibition exhibits pleiotropic effects that combine direct cytotoxicity with increased surface CD20 levels and increased susceptibility to anti-CD20 antibody-based therapies. Study supported by Foundation for Polish Science (POIR.04.04.00-00-5C84/17-00), Polish National Science Centre (2016/22/M/NZ5/00668 and 2017/26/D/NZ5/00561) and Ministry of Science and Higher Education in Poland (iONCO) grants. Disclosures Golas: Ryvu Therapeutics: Current Employment. Green:KDAc Therapeutics: Current equity holder in private company. Tomirotti:Menarini Ricerche: Current Employment. Brzózka:Ryvu Therapeutics: Current Employment. Juszczynski:Ryvu Therapeutics: Other: member of advisory board.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-134778
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
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    HDAC6 Inhibition Increases Translation of CD20 mRNA and Potentiates the Efficacy of Anti-CD20 Immunotherapy
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 1586-1586
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1586-1586
    Abstract: Down-regulation of CD20, a molecular target for monoclonal antibodies, is a clinical problem leading to decreased efficacy of anti-CD20-based regimens. Moreover, a substantial number of patients do not fully benefit from anti-CD20 immunotherapy due to the low CD20 expression. It has been shown that histone deacetylase inhibitors (HDACi), in a transcription-dependent mechanism, regulate CD20 surface level. However, non-specific HDAC pan-inhibitors have considerable number of side effects, therefore a new isoform-specific inhibitors are being developed. Recently, HDAC6-selective inhibitors have emerged in non-Hodgkin lymphoma and chronic lymphocytic leukemia (CLL) potential therapies. Preclinical data show therapeutic potential of HDAC6 inhibitors in combination approach. However, their effect on the efficacy of anti-CD20 immunotherapy has not been studied so far. Therefore, this study aimed to investigate the influence of HDAC6 inhibition on the regulation of CD20 expression. This study was performed in in vitro settings using a panel of established B-cell-derived tumors (Raji, Daudi, Ly-1, Karpas) as well as EBV-transformed cells and CLL primary samples. Commercial HDAC6 inhibitors- tubacin, tubastatin and clinically available ricolinostat (ACY1215) were used. In order to silence HDAC6 expression we used shRNA. The expression levels of surface antigens were assessed by flow cytometry. Total protein level was assessed by Western blotting. The influence of HDAC6 inhibition on transcription of CD20 mRNA was analyzed in qRT-PCR. In order to investigate the stability of CD20 protein a cycloheximide chase assay has been employed. The synthesis of protein de novo was investigated using Click-chemistry. To investigate the impact of HDAC6 inhibition on translation of CD20 mRNA polysomes were isolated. In this study using pharmacological inhibitors and genetic modification we have shown that HDAC6 inhibition significantly increases CD20 level in a panel of B-cell derived human tumor cell lines as well as in primary CLL samples. The observed upregulation of CD20 correlates with sensitization to type I and type II anti-CD20 antibodies. We observed that HDAC6 inhibition increases total CD20 protein level without affecting its mRNA level or promoter activity. As HDAC6 has been shown to regulate protein trafficking and degradation, we performed experiments assessing the influence of HDAC6 inhibition on CD20 endocytosis. We concluded that HDAC6 inhibition does not alter the internalization rate of CD20. In cycloheximide chase assay we showed that CD20 is a rather stable protein and therefore hypothesized that HDAC6 inhibition may be a consequence of increased translation of CD20 mRNA. Using Click-it metabolic labelling we concluded that HDAC6 inhibition significantly increased the production of CD20 de novo. To substantiate our findings on increased translation of CD20 after HDAC6 inhibition, we performed polysomal profiling followed by qRT-PCR on polysomal extracts from Raji cells. We observed no considerable changes in polysomal profiling curves between control and tubacin- pretreated cells further confirming that tubacin did not alter the overall level of protein translation. Importantly, our findings showed a significant increase in CD20 mRNA in polysomal fraction in tubacin-treated group when compared with control cells. Altogether, our results clearly indicate that HDAC6 is involve in posttranscriptional regulation of CD20 and HDAC6 inhibition increases the translational efficiency of CD20 mRNA. Our results strongly support that HDAC6 inhibition can be a therapeutic strategy successfully enhancing the efficacy of anti-CD20 mAbs. Our pre-clinical investigation might be relevant in terms of designing clinical combination studies and support further use of HDAC6 inhibitors in combination with anti-CD20 mAbs. Figure Polysomal profiling. Cytosolic lysates from control and tubacin- pretreated Raji cells were prepared in lysis buffer followed by two centrifugations. Cytosolic proteins were layered onto linear sucrose gradient and sedimented by a 2h centrifugation. The gradients were collected in 15 fractions and absorbance profiles were generated at 254 nm (A). Polysomal fractions were pooled for further RNA extraction and quantitative PCR (B). Figure. Polysomal profiling. / Cytosolic lysates from control and tubacin- pretreated Raji cells were prepared in lysis buffer followed by two centrifugations. Cytosolic proteins were layered onto linear sucrose gradient and sedimented by a 2h centrifugation. The gradients were collected in 15 fractions and absorbance profiles were generated at 254 nm (A). Polysomal fractions were pooled for further RNA extraction and quantitative PCR (B). Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.1586.1586
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
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    Functional characterization of the interactions between endosomal adaptor protein APPL1 and the NuRD co-repressor complex
    Portland Press Ltd. ; 2009
    In:  Biochemical Journal Vol. 423, No. 3 ( 2009-11-01), p. 389-400
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 423, No. 3 ( 2009-11-01), p. 389-400
    Abstract: Multifunctional adaptor protein APPL1 [adaptor protein containing PH (pleckstrin homology) domain, PTB (phosphotyrosine binding) domain and leucine zipper motif] belongs to a growing group of endocytic proteins which actively participate in various stages of signalling pathways. Owing to its interaction with the small GTPase Rab5, APPL1 localizes predominantly to a subpopulation of early endosomes but is also capable of nucleocytoplasmic shuttling. Among its various binding partners, APPL1 was reported to associate with the nuclear co-repressor complex NuRD (nucleosome remodelling and deacetylase), containing both nucleosome remodelling and HDAC (histone deacetylase) activities, but the biochemical basis or functional relevance of this interaction remained unknown. Here we characterized the binding between APPL1 and NuRD in more detail, identifying HDAC2 as the key NuRD subunit responsible for this association. APPL1 interacts with the NuRD complex containing enzymatically active HDAC2 but not HDAC1 as the only deacetylase. However, the cellular levels of HDAC1 can regulate the extent of APPL1–NuRD interactions, which in turn modulates the nucleocytoplasmic distribution of APPL1. Increased binding of APPL1 to NuRD upon silencing of HDAC1 promotes the nuclear localization of APPL1, whereas HDAC1 overexpression exerts an opposite effect. Moreover, we also uncovered a NuRD-independent interaction of APPL1 with HDAC1. APPL1 overexpression affects the composition of the HDAC1-containing NuRD complex and the expression of HDAC1 target p21WAF1/CIP1. Cumulatively, these data reveal a surprising complexity of APPL1 interactions with HDACs, with functional consequences for the modulation of gene expression. In a broader sense, these results contribute to an emerging theme of endocytic proteins playing alternative roles in the cell nucleus.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20090086
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2009
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 6
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    Abstract B17: FOXO1 is transcriptional regulator of malignant B-cell surface antigen CD20, the target for therapeutic monoclonal antibodies
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Immunology Research Vol. 6, No. 9_Supplement ( 2018-09-01), p. B17-B17
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 6, No. 9_Supplement ( 2018-09-01), p. B17-B17
    Abstract: Rituximab, a therapeutic anti-CD20 monoclonal antibody, is effective against B-cell malignancies, when combined with chemotherapy, such as cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP therapy). However, in case of 30-40% patients the resistance to rituximab-based therapy appears to be a serious concern. One of the major mechanisms of resistance relies on the reduced level of CD20 antigen on the surface of tumor B-cells. While exploring the molecular mechanisms affecting the level of CD20, we found that transcription factor FOXO1 is a negative regulator of MS4A1 expression, the gene encoding CD20 antigen. Using the CRISPR/Cas9 genome-editing technology, we disrupted the loci of FOXO genes in lymphoma cell lines and discovered that ablation of FOXO1 (but not FOXO3) was sufficient for upregulation of the surface level of CD20 by 3-fold. Consistently, the complement-dependent cytotoxicity (CDC), induced by rituximab, was significantly improved in cell clones with abrogated expression of FOXO1, but not FOXO3. Importantly, the treatment with pharmacological inhibitor of FOXO1 activity, AS1842856, resulted in increased levels of CD20 on the surface of both lymphoma cell lines and patients-derived chronic lymphocytic leukemia (CLL) cells cultured ex vivo. In order to verify our findings in the animal model, we inoculated SCID mice intravenously with Raji cells, what resulted in the development of lymphoma-like tumors. We demonstrated that mice treated systemically with rituximab, administered at a dose of 10 mg/kg, survived longer when inoculated with sgFOXO1-transduced Raji cells as compared with mice inoculated with control Raji cells (median survival 49 days versus 29 days, respectively). These results confirmed that FOXO1 ablation in lymphoma cells resulted in higher efficacy of rituximab treatment in vivo. Taken together, these results establish FOXO1 as an important determinant of cell response to complement-dependent rituximab-induced cytotoxicity and indicate that FOXO1 inhibitors could be exploited for the therapeutic purposes, in combination with anti-CD20 monoclonal antibodies. Novel FOXO1 inhibitors with improved potency and selectivity are however urgently needed for further exploration of our discoveries in the near future. Acknowledgments: NCN, Poland (grant no: 2013/11/B/NZ5/03240) and H2020 (STREAM project, CSA action, grant no: 692180). Citation Format: Beata Pyrzynska, Abdessamad Zerrouqi, Michal Dwojak, Giulia Morlino, Piotr Zapala, Nina Miazek, Agnieszka Zagozdzon, Kamil Bojarczuk, Malgorzata Bobrowicz, Marta Siernicka, Marcin M. Machnicki, Joanna Barankiewicz, Ewa Lech-Maranda, Przemyslaw Juszczynski, Dinis Calado, Jakub Golab, Magdalena Winiarska. FOXO1 is transcriptional regulator of malignant B-cell surface antigen CD20, the target for therapeutic monoclonal antibodies [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B17.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.TUMIMM17-B17
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2732517-9
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  • 7
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    Abstract B14: Natural killer immune response is promoted by the treatment of B-cell lymphoma cancer cells with membrane ionophores
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Immunology Research Vol. 8, No. 3_Supplement ( 2020-03-01), p. B14-B14
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 8, No. 3_Supplement ( 2020-03-01), p. B14-B14
    Abstract: Introduction: Over the last two decades, very compelling clinical and experimental evidences have accelerated the use of natural killer (NK) cells’ properties for the recognition and eradication of hematologic malignancies. NK cells mediate antitumor killing responses via antibody-dependent cell-mediated cytotoxicity (ADCC). In order to accelerate and sustain NK antitumor immunity, antibodies targeting antigens expressed on the membrane surface of cancer cells are used as therapeutic interventions. Here, we investigated the antitumor benefit of the combination of the therapeutic anti-CD20 antibody, rituximab, with shortlisted membrane ionophores to overcome the resistance of B-cell lymphomas toward anti-CD20 targeted monoclonal antibodies. Methods: Flow cytometry was used to quantify cell surface protein levels and the rate of tumor cell death. Serum and PBMCs of human healthy donors were used as source of complement and natural killer cells, respectively. ADCC, complement-dependent cytotoxicity (CDC), and degranulation assays were used to assess the sensitivity of NHL cell lines and primary cancer cells upon treatment with ionophores plus rituximab. RNA-seq and qPCR were used to identify and confirm the deferentially expressed genes upon ionophores treatment. GSEA, an online resource of the Broad Institute (Boston, MA), was used to screen the differentially expressed genes and major signaling pathways. Results: Our data show that the sublethal doses of these ionophores ( & lt; 0.5uM) greatly increased surface CD20 (protein target for rituximab therapy) levels onB-cell lymphoma (Burkitt and DLBCL) cell lines. B-cell lymphoma cell death induced by rituximab, either mediated by complement or NK cell cytotoxicities, was significantly increased upon treatment with ionophores. These in vitro effects have been confirmed in xenograft model in SCID mice. While rituximab treatment alone slightly delayed tumor growth, the combination of rituximab with ionophores caused a dramatic decrease (up to 3x) of tumor size. The anticipated signaling pathways influencing NK cell activity are currently being interrogated; transcriptomic analysis combined with GSEA will allow to identify markedly altered pathways that are potentially closely involved in enhancing the sensitivity of rituximab-treated B-cell lymphoma cells. Summary: The data indicate that ionophores are promising therapeutic agents that could strongly enhance CD20 expression on the surface of target tumor cells. When combined with therapeutic anti-CD20 monoclonal antibodies, impressive high NK cell-mediated cytotoxicity is demonstrated that potentially offsets the B lymphoma resistance to R-CHOP regimen. These results also support the clinical development of these molecules as adjuvant to existing cancer immunotherapies. Support: National Science Centre (NCN, Poland), ID: 2016/23/B/NZ5/02622; Ministry of Science and Higher Education in Poland, ID: DI2014007344 and iONKO grant. Citation Format: Abdessamad Zerrouqi, Anna Torun, Nina Miazek, Zofia Pilch, Jakub Golab, Beata Pyrzynska. Natural killer immune response is promoted by the treatment of B-cell lymphoma cancer cells with membrane ionophores [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B14.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.TUMIMM19-B14
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 8
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    Abstract 3845: Endocytic protein APPL2 as a regulator of glioblastoma cell growth
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3845-3845
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3845-3845
    Abstract: Recent discoveries have suggested that some endocytic proteins are involved in multiple steps of cellular signaling, which starts from endocytosis of activated receptors and is further transmitted from the cytoplasm to the nucleus. Two homologous adaptor proteins APPL1 and APPL2 seem to constitute good examples of such proteins, involved in both endocytosis (by interacting with small GTPase Rab5) and cellular signaling. They are able to translocate to the nucleus and may participate in the regulation of chromatin modification, raising a possibility of their involvement in the control of gene transcription. Deregulation of such important cellular functions may be a cause of neoplastic growth and tumorigenesis. In fact, there are some lines of evidence suggesting a possible role for APPL proteins in cancer development and/or progression: 1) APPL proteins participate in endocytic trafficking of several transmembrane receptors and defective degradation (via deregulation of endocytosis) of the receptor tyrosine kinases, like EGFR, leads to sustained signaling, changes in cell proliferation or transformation; 2) APPL proteins can also increase activity the key kinase involved in the regulation of tumorigenesis – AKT, by interacting with several components of its signaling pathway, like PI3K, AKT itself, GSK3β and TSC2. Indeed both APPL proteins appear to be required for HGF-induced cell survival and migration via activation of AKT. Many major genomic abnormalities in human glioblastoma (GBM) samples, recently cataloged by the TCGA Research Network, result in aberrations of signaling molecules and pathways potentially regulated by APPL proteins, like receptor tyrosine kinases and AKT, highlighting their importance for GBM development. Taking in consideration all the facts mentioned above, we have chosen GBM as a model to study the potential role of APPL proteins in the regulation of tumor growth. During our study we have discovered the following phenomena: i) The level of APPL2 protein (but not APPL1) is significantly increased in 40% of human GBM versus normal brain samples. ii) Silencing of APPL2 in GBM cell lines decreases both anchorage-independent growth and cell viability under reduced growth factor availability. These effects result from both: inhibition of cell proliferation and increased apoptosis. iii) Expression of some cell cycle- and apoptosis-related genes changes upon APPL2 silencing. To our knowledge these results for the first time show the upregulation of APPL2 protein in human tumor samples suggesting that this protein may provide some advantage for tumor growth. The results of in vitro experiments explain the mechanism by demonstrating that APPL2 influences both cell proliferation and resistance to apoptosis. Our results also highlight the surprising differences in the functions of homologous APPL1 and APPL2 proteins that will be further discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3845. doi:10.1158/1538-7445.AM2011-3845
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-3845
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
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    Abstract LB-261: Salinomycin expands the cytotoxicity of both anti-CD20 monoclonal antibodies and natural killer cells towards non-Hodgkin lymphomas
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. LB-261-LB-261
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. LB-261-LB-261
    Abstract: The primary hurdle in non-Hodgkin lymphoma (NHL) treatment is the resistance to the recommended R-CHOP regimen which is composed of anti-CD20-targeted immunotherapy, Rituximab or RTX, and multiple chemotherapeutic drugs: cyclophosphamide, doxorubicin, vincristine and prednisone. In many patients, the resistance is correlated to the reduced level of CD20 antigen on the surface of tumor B cells. While testing drugs that overcome this resistance, we sought of testing whether Salinomycin, a drug that preferentially act on cancer cells over healthy cells, and selectively target cancer stem cells, is able to improve the sensitivity of NHL to Rituximab. Herein, we investigated its effect on NK cell- and complement-dependent cytotoxicity on NHL cells and its mechanism of action. Methods: Antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and degranulation assays were used to assess the sensitivity of NHL cell lines and primary cancer cells upon treatment with salinomycin plus rituximab. Serum and PBMCs of human healthy donors were used as source of complement and Natural Killer cells, respectively. Flow cytometry was used to quantify cell death rate and cell surface protein levels. RNA-seq and qPCR were used to identify and confirm the differentially expressed genes upon salinomycin treatment. GSEA, an online resource of the Broad Institute MA, was used to screen the differentially expressed genes and major signaling pathways. Results and Conclusions: In addition to previously reported ability of Salinomycin to kill cancer stem cells, our data show that the sub-lethal doses of Salinomycin greatly increased surface CD20 (protein target for Rituximab therapy) on both lymphoma cell lines and primary CLL samples. Lymphoma cell death induced by rituximab and mediated by complement and NK cell cytotoxicities was significantly increased upon treatment with salinomycin. Transcriptomic analysis of cells treated with salinomycin identified a sets of differentially expressed genes (including CD20-encoding gene) and markedly activated/affected pathways that are potentially involved in enhancing the sensitivity of Rituximab-treated NHL cells. The anticipated signaling pathways influencing NK cell activity will be further examined. These data indicate that salinomycin is an interesting therapeutic agent when combined with therapeutic anti-CD20 monoclonal antibodies. This particular combination would ensure higher NK cell-mediated cytotoxicity and offset the NHL resistance to R-CHOP regimen. Aknowledgements: National Science Centre (NCN), ID: 2016/23/B/NZ5/02622; Ministry of Science and Higher Education, ID: DI2014007344. Citation Format: Abdessamad Zerrouqi, Nina Miazek-Zapala, Anna Torun, Piotr Zapala, Jakub Golab, Magdalena Winiarska, Beata Pyrzynska. Salinomycin expands the cytotoxicity of both anti-CD20 monoclonal antibodies and natural killer cells towards non-Hodgkin lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-261.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-LB-261
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
    Online Resource
    Online Resource
    Inhibition of PIM Kinases in DLBCL Targets MYC Transcriptional Program and Augments the Efficacy of Anti-CD20 Antibodies
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 23 ( 2021-12-01), p. 6029-6043
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 23 ( 2021-12-01), p. 6029-6043
    Abstract: The family of PIM serine/threonine kinases includes three highly conserved oncogenes, PIM1, PIM2, and PIM3, which regulate multiple prosurvival pathways and cooperate with other oncogenes such as MYC. Recent genomic CRISPR-Cas9 screens further highlighted oncogenic functions of PIMs in diffuse large B-cell lymphoma (DLBCL) cells, justifying the development of small-molecule PIM inhibitors and therapeutic targeting of PIM kinases in lymphomas. However, detailed consequences of PIM inhibition in DLBCL remain undefined. Using chemical and genetic PIM blockade, we comprehensively characterized PIM kinase–associated prosurvival functions in DLBCL and the mechanisms of PIM inhibition–induced toxicity. Treatment of DLBCL cells with SEL24/MEN1703, a pan-PIM inhibitor in clinical development, decreased BAD phosphorylation and cap-dependent protein translation, reduced MCL1 expression, and induced apoptosis. PIM kinases were tightly coexpressed with MYC in diagnostic DLBCL biopsies, and PIM inhibition in cell lines and patient-derived primary lymphoma cells decreased MYC levels as well as expression of multiple MYC-dependent genes, including PLK1. Chemical and genetic PIM inhibition upregulated surface CD20 levels in an MYC-dependent fashion. Consistently, MEN1703 and other clinically available pan-PIM inhibitors synergized with the anti-CD20 monoclonal antibody rituximab in vitro, increasing complement-dependent cytotoxicity and antibody-mediated phagocytosis. Combined treatment with PIM inhibitor and rituximab suppressed tumor growth in lymphoma xenografts more efficiently than either drug alone. Taken together, these results show that targeting PIM in DLBCL exhibits pleiotropic effects that combine direct cytotoxicity with potentiated susceptibility to anti-CD20 antibodies, justifying further clinical development of such combinatorial strategies. Significance: These findings demonstrate that inhibition of PIM induces DLBCL cell death via MYC-dependent and -independent mechanisms and enhances the therapeutic response to anti-CD20 antibodies by increasing CD20 expression.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-21-1023
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
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