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Somadder PD, Hossain MA, Ahsan A, Sultana T, Soikot SH, Rahman MM, Ibrahim SM, Ahmed K, Bui FM. Drug Repurposing and Systems Biology approaches of Enzastaurin can target potential biomarkers and critical pathways in Colorectal Cancer. Comput Biol Med 2023; 155:106630. [PMID: 36774894 DOI: 10.1016/j.compbiomed.2023.106630] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 01/28/2023] [Accepted: 02/04/2023] [Indexed: 02/10/2023]
Abstract
Colorectal cancer (CRC) is a severe health concern that results from a cocktail of genetic, epigenetic, and environmental abnormalities. Because it is the second most lethal malignancy in the world and the third-most common malignant tumor, but the treatment is unavailable. The goal of the current study was to use bioinformatics and systems biology techniques to determine the pharmacological mechanism underlying putative important genes and linked pathways in early-onset CRC. Computer-aided methods were used to uncover similar biological targets and signaling pathways associated with CRC, along with bioinformatics and network pharmacology techniques to assess the effects of enzastaurin on CRC. The KEGG and gene ontology (GO) pathway analysis revealed several significant pathways including in positive regulation of protein phosphorylation, negative regulation of the apoptotic process, nucleus, nucleoplasm, protein tyrosine kinase activity, PI3K-Akt signaling pathway, pathways in cancer, focal adhesion, HIF-1 signaling pathway, and Rap1 signaling pathway. Later, the hub protein module identified from the protein-protein interactions (PPIs) network, molecular docking and molecular dynamics simulation represented that enzastaurin showed strong binding interaction with two hub proteins including CASP3 (-8.6 kcal/mol), and MCL1 (-8.6 kcal/mol), which were strongly implicated in CRC management than other the five hub proteins. Moreover, the pharmacokinetic features of enzastaurin revealed that it is an effective therapeutic agent with minimal adverse effects. Enzastaurin may inhibit the potential biological targets that are thought to be responsible for the advancement of CRC and this study suggests a potential novel therapeutic target for CRC.
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Affiliation(s)
- Pratul Dipta Somadder
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Tangail, 1092, Bangladesh.
| | - Md Arju Hossain
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Tangail, 1092, Bangladesh.
| | - Asif Ahsan
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Tangail, 1092, Bangladesh.
| | - Tayeba Sultana
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Tangail, 1092, Bangladesh.
| | - Sadat Hossain Soikot
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Tangail, 1092, Bangladesh.
| | - Md Masuder Rahman
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Tangail, 1092, Bangladesh.
| | - Sobhy M Ibrahim
- Department of Biochemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia.
| | - Kawsar Ahmed
- Department of Electrical and Computer Engineering, University of Saskatchewan, 57 Campus Drive, Saskatoon, SK, S7N 5A9, Canada; Group of Biophotomatiχ, Department of Information and Communication Technology, Mawlana Bhashani Science and Technology University, Santosh, Tangail, 1902, Bangladesh.
| | - Francis M Bui
- Department of Electrical and Computer Engineering, University of Saskatchewan, 57 Campus Drive, Saskatoon, SK, S7N 5A9, Canada.
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Nasimian A, Al Ashiri L, Ahmed M, Duan H, Zhang X, Rönnstrand L, Kazi JU. A Receptor Tyrosine Kinase Inhibitor Sensitivity Prediction Model Identifies AXL Dependency in Leukemia. Int J Mol Sci 2023; 24:ijms24043830. [PMID: 36835239 PMCID: PMC9959897 DOI: 10.3390/ijms24043830] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/05/2023] [Accepted: 02/11/2023] [Indexed: 02/17/2023] Open
Abstract
Despite incredible progress in cancer treatment, therapy resistance remains the leading limiting factor for long-term survival. During drug treatment, several genes are transcriptionally upregulated to mediate drug tolerance. Using highly variable genes and pharmacogenomic data for acute myeloid leukemia (AML), we developed a drug sensitivity prediction model for the receptor tyrosine kinase inhibitor sorafenib and achieved more than 80% prediction accuracy. Furthermore, by using Shapley additive explanations for determining leading features, we identified AXL as an important feature for drug resistance. Drug-resistant patient samples displayed enrichment of protein kinase C (PKC) signaling, which was also identified in sorafenib-treated FLT3-ITD-dependent AML cell lines by a peptide-based kinase profiling assay. Finally, we show that pharmacological inhibition of tyrosine kinase activity enhances AXL expression, phosphorylation of the PKC-substrate cyclic AMP response element binding (CREB) protein, and displays synergy with AXL and PKC inhibitors. Collectively, our data suggest an involvement of AXL in tyrosine kinase inhibitor resistance and link PKC activation as a possible signaling mediator.
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Affiliation(s)
- Ahmad Nasimian
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, 22381 Lund, Sweden
- Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, 22184 Lund, Sweden
| | - Lina Al Ashiri
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, 22381 Lund, Sweden
- Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, 22184 Lund, Sweden
| | - Mehreen Ahmed
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, 22381 Lund, Sweden
- Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, 22184 Lund, Sweden
| | - Hongzhi Duan
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, 22381 Lund, Sweden
- Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, 22184 Lund, Sweden
| | - Xiaoyue Zhang
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, 22381 Lund, Sweden
- Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, 22184 Lund, Sweden
| | - Lars Rönnstrand
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, 22381 Lund, Sweden
- Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, 22184 Lund, Sweden
- Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, 22185 Lund, Sweden
| | - Julhash U. Kazi
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, 22381 Lund, Sweden
- Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, 22184 Lund, Sweden
- Correspondence: ; Tel.: +46-462226407
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3
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Immanuel T, Li J, Green TN, Bogdanova A, Kalev-Zylinska ML. Deregulated calcium signaling in blood cancer: Underlying mechanisms and therapeutic potential. Front Oncol 2022; 12:1010506. [PMID: 36330491 PMCID: PMC9623116 DOI: 10.3389/fonc.2022.1010506] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/21/2022] [Indexed: 02/05/2023] Open
Abstract
Intracellular calcium signaling regulates diverse physiological and pathological processes. In solid tumors, changes to calcium channels and effectors via mutations or changes in expression affect all cancer hallmarks. Such changes often disrupt transport of calcium ions (Ca2+) in the endoplasmic reticulum (ER) or mitochondria, impacting apoptosis. Evidence rapidly accumulates that this is similar in blood cancer. Principles of intracellular Ca2+ signaling are outlined in the introduction. We describe different Ca2+-toolkit components and summarize the unique relationship between extracellular Ca2+ in the endosteal niche and hematopoietic stem cells. The foundational data on Ca2+ homeostasis in red blood cells is discussed, with the demonstration of changes in red blood cell disorders. This leads to the role of Ca2+ in neoplastic erythropoiesis. Then we expand onto the neoplastic impact of deregulated plasma membrane Ca2+ channels, ER Ca2+ channels, Ca2+ pumps and exchangers, as well as Ca2+ sensor and effector proteins across all types of hematologic neoplasms. This includes an overview of genetic variants in the Ca2+-toolkit encoding genes in lymphoid and myeloid cancers as recorded in publically available cancer databases. The data we compiled demonstrate that multiple Ca2+ homeostatic mechanisms and Ca2+ responsive pathways are altered in hematologic cancers. Some of these alterations may have genetic basis but this requires further investigation. Most changes in the Ca2+-toolkit do not appear to define/associate with specific disease entities but may influence disease grade, prognosis, treatment response, and certain complications. Further elucidation of the underlying mechanisms may lead to novel treatments, with the aim to tailor drugs to different patterns of deregulation. To our knowledge this is the first review of its type in the published literature. We hope that the evidence we compiled increases awareness of the calcium signaling deregulation in hematologic neoplasms and triggers more clinical studies to help advance this field.
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Affiliation(s)
- Tracey Immanuel
- Blood and Cancer Biology Laboratory, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
| | - Jixia Li
- Blood and Cancer Biology Laboratory, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
- Department of Laboratory Medicine, School of Medicine, Foshan University, Foshan City, China
| | - Taryn N. Green
- Blood and Cancer Biology Laboratory, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
| | - Anna Bogdanova
- Red Blood Cell Research Group, Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zürich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zürich, Switzerland
| | - Maggie L. Kalev-Zylinska
- Blood and Cancer Biology Laboratory, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
- Haematology Laboratory, Department of Pathology and Laboratory Medicine, Auckland City Hospital, Auckland, New Zealand
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Cytotoxicity of Thioalkaloid-Enriched Nuphar lutea Extract and Purified 6,6′-Dihydroxythiobinupharidine in Acute Myeloid Leukemia Cells: The Role of Oxidative Stress and Intracellular Calcium. Pharmaceuticals (Basel) 2022; 15:ph15040410. [PMID: 35455407 PMCID: PMC9032197 DOI: 10.3390/ph15040410] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/20/2022] [Accepted: 03/23/2022] [Indexed: 11/17/2022] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by uncontrolled proliferation of immature myeloid progenitors. Here, we report the in vitro antileukemic effects of the sesquiterpene thioalkaloid-enriched fraction of the Nuphar lutea leaf extract (NUP) and a purified thioalkaloid 6,6′-dihydroxythiobinupharidine (DTBN). Treatment with 0.3–10 µg/mL NUP caused a dose- and time-dependent reduction in proliferation and viability of human AML cells (KG-1a, HL60 and U937). This was associated with apoptosis induction manifested by annexin-V/propidium iodide binding as well as cleavage of caspases 8, 9, and 3 as well as poly (ADP-ribose) polymerase. Caspase-dependence of the apoptotic effect was confirmed using the pan-caspase inhibitor Q-VD-OPH. NUP induced significant biphasic changes in the cytosolic levels of reactive oxygen species (ROS) compared to untreated cells—a decrease at early time points (2–4 h) and an increase after a longer incubation (24 h). ROS accumulation was accompanied by lowering the cellular glutathione (GSH) levels. In addition, NUP treatment resulted in elevation of the cytosolic Ca2+ (Ca2+cyt) levels. The thiol antioxidant and glutathione precursor N-acetyl cysteine prevented NUP-induced ROS accumulation and markedly inhibited apoptosis. A similar antiapoptotic effect was obtained by Ca2+cyt chelating using BAPTA. These data indicate that NUP-induced cell death is mediated, at least in part, by the induction of oxidative stress and Ca2+cyt accumulation. However, a substantial apoptotic activity of pure DTBN (0.05–0.25 µg/mL), was found to be independent of cytosolic ROS or Ca2+, suggesting that alternative mechanisms are involved in DTBN-induced cytotoxicity. Notably, neither NUP nor DTBN treatment significantly induced cell death of normal human peripheral blood mononuclear cells. Our results provide the basis for further investigation of the antileukemic potential of NUP and its active constituents.
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Shah K, Kazi JU. Phosphorylation-Dependent Regulation of WNT/Beta-Catenin Signaling. Front Oncol 2022; 12:858782. [PMID: 35359365 PMCID: PMC8964056 DOI: 10.3389/fonc.2022.858782] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 02/16/2022] [Indexed: 01/11/2023] Open
Abstract
WNT/β-catenin signaling is a highly complex pathway that plays diverse roles in various cellular processes. While WNT ligands usually signal through their dedicated Frizzled receptors, the decision to signal in a β-catenin-dependent or -independent manner rests upon the type of co-receptors used. Canonical WNT signaling is β-catenin-dependent, whereas non-canonical WNT signaling is β-catenin-independent according to the classical definition. This still holds true, albeit with some added complexity, as both the pathways seem to cross-talk with intertwined networks that involve the use of different ligands, receptors, and co-receptors. β-catenin can be directly phosphorylated by various kinases governing its participation in either canonical or non-canonical pathways. Moreover, the co-activators that associate with β-catenin determine the output of the pathway in terms of induction of genes promoting proliferation or differentiation. In this review, we provide an overview of how protein phosphorylation controls WNT/β-catenin signaling, particularly in human cancer.
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Affiliation(s)
- Kinjal Shah
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Julhash U. Kazi
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden
- *Correspondence: Julhash U. Kazi,
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Protein Kinase C as a Therapeutic Target in Non-Small Cell Lung Cancer. Int J Mol Sci 2021; 22:ijms22115527. [PMID: 34073823 PMCID: PMC8197251 DOI: 10.3390/ijms22115527] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 05/19/2021] [Accepted: 05/20/2021] [Indexed: 12/30/2022] Open
Abstract
Driver-directed therapeutics have revolutionized cancer treatment, presenting similar or better efficacy compared to traditional chemotherapy and substantially improving quality of life. Despite significant advances, targeted therapy is greatly limited by resistance acquisition, which emerges in nearly all patients receiving treatment. As a result, identifying the molecular modulators of resistance is of great interest. Recent work has implicated protein kinase C (PKC) isozymes as mediators of drug resistance in non-small cell lung cancer (NSCLC). Importantly, previous findings on PKC have implicated this family of enzymes in both tumor-promotive and tumor-suppressive biology in various tissues. Here, we review the biological role of PKC isozymes in NSCLC through extensive analysis of cell-line-based studies to better understand the rationale for PKC inhibition. PKC isoforms α, ε, η, ι, ζ upregulation has been reported in lung cancer, and overexpression correlates with worse prognosis in NSCLC patients. Most importantly, PKC isozymes have been established as mediators of resistance to tyrosine kinase inhibitors in NSCLC. Unfortunately, however, PKC-directed therapeutics have yielded unsatisfactory results, likely due to a lack of specific evaluation for PKC. To achieve satisfactory results in clinical trials, predictive biomarkers of PKC activity must be established and screened for prior to patient enrollment. Furthermore, tandem inhibition of PKC and molecular drivers may be a potential therapeutic strategy to prevent the emergence of resistance in NSCLC.
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7
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Signal Transduction in Immune Cells and Protein Kinases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1275:133-149. [PMID: 33539014 DOI: 10.1007/978-3-030-49844-3_5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Immune response relies upon several intracellular signaling events. Among the protein kinases involved in these pathways, members of the protein kinase C (PKC) family are prominent molecules because they have the capacity to acutely and reversibly modulate effector protein functions, controlling both spatial distribution and dynamic properties of the signals. Different PKC isoforms are involved in distinct signaling pathways, with selective functions in a cell-specific manner.In innate system, Toll-like receptor signaling is the main molecular event triggering effector functions. Various isoforms of PKC can be common to different TLRs, while some of them are specific for a certain type of TLR. Protein kinases involvement in innate immune cells are presented within the chapter emphasizing their coordination in many aspects of immune cell function and, as important players in immune regulation.In adaptive immunity T-cell receptor and B-cell receptor signaling are the main intracellular pathways involved in seminal immune specific cellular events. Activation through TCR and BCR can have common intracellular pathways while others can be specific for the type of receptor involved or for the specific function triggered. Various PKC isoforms involvement in TCR and BCR Intracellular signaling will be presented as positive and negative regulators of the immune response events triggered in adaptive immunity.
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8
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Ma D, Wang P, Fang Q, Yu Z, Zhou Z, He Z, Wei D, Yu K, Lu T, Zhang Y, Wang J. Low-dose staurosporine selectively reverses BCR-ABL-independent IM resistance through PKC-α-mediated G2/M phase arrest in chronic myeloid leukaemia. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 46:S208-S216. [PMID: 30618318 DOI: 10.1080/21691401.2018.1490310] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Dan Ma
- Department of Hematology, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province, Affiliated Hospital of Guizhou Medical University, Guizhou Province Institute of Hematology, Guiyang, China
| | - Ping Wang
- Department of Hematology, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province, Affiliated Hospital of Guizhou Medical University, Guizhou Province Institute of Hematology, Guiyang, China
| | - Qin Fang
- Department of Pharmacy, Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang, China
- Department of Pharmacy, Affiliated Hospital of Guiyang Medical University, Guiyang, China
| | - Zhengyu Yu
- Department of Hematology, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province, Affiliated Hospital of Guizhou Medical University, Guizhou Province Institute of Hematology, Guiyang, China
| | - Zhen Zhou
- Department of Hematology, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province, Affiliated Hospital of Guizhou Medical University, Guizhou Province Institute of Hematology, Guiyang, China
- Department of Pharmacy, Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang, China
- Department of Pharmacy, Affiliated Hospital of Guiyang Medical University, Guiyang, China
| | - Zhengchang He
- Department of Hematology, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province, Affiliated Hospital of Guizhou Medical University, Guizhou Province Institute of Hematology, Guiyang, China
| | - Danna Wei
- Department of Hematology, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province, Affiliated Hospital of Guizhou Medical University, Guizhou Province Institute of Hematology, Guiyang, China
| | - Kunling Yu
- Department of Hematology, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province, Affiliated Hospital of Guizhou Medical University, Guizhou Province Institute of Hematology, Guiyang, China
| | - Tingting Lu
- Department of Hematology, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province, Affiliated Hospital of Guizhou Medical University, Guizhou Province Institute of Hematology, Guiyang, China
| | - Yaming Zhang
- Department of Hematology, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province, Affiliated Hospital of Guizhou Medical University, Guizhou Province Institute of Hematology, Guiyang, China
| | - Jishi Wang
- Department of Hematology, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province, Affiliated Hospital of Guizhou Medical University, Guizhou Province Institute of Hematology, Guiyang, China
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Darwiche W, Gubler B, Marolleau JP, Ghamlouch H. Chronic Lymphocytic Leukemia B-Cell Normal Cellular Counterpart: Clues From a Functional Perspective. Front Immunol 2018; 9:683. [PMID: 29670635 PMCID: PMC5893869 DOI: 10.3389/fimmu.2018.00683] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 03/20/2018] [Indexed: 12/20/2022] Open
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of small mature-looking CD19+ CD23+ CD5+ B-cells that accumulate in the blood, bone marrow, and lymphoid organs. To date, no consensus has been reached concerning the normal cellular counterpart of CLL B-cells and several B-cell types have been proposed. CLL B-cells have remarkable phenotypic and gene expression profile homogeneity. In recent years, the molecular and cellular biology of CLL has been enriched by seminal insights that are leading to a better understanding of the natural history of the disease. Immunophenotypic and molecular approaches (including immunoglobulin heavy-chain variable gene mutational status, transcriptional and epigenetic profiling) comparing the normal B-cell subset and CLL B-cells provide some new insights into the normal cellular counterpart. Functional characteristics (including activation requirements and propensity for plasma cell differentiation) of CLL B-cells have now been investigated for 50 years. B-cell subsets differ substantially in terms of their functional features. Analysis of shared functional characteristics may reveal similarities between normal B-cell subsets and CLL B-cells, allowing speculative assignment of a normal cellular counterpart for CLL B-cells. In this review, we summarize current data regarding peripheral B-cell differentiation and human B-cell subsets and suggest possibilities for a normal cellular counterpart based on the functional characteristics of CLL B-cells. However, a definitive normal cellular counterpart cannot be attributed on the basis of the available data. We discuss the functional characteristics required for a cell to be logically considered to be the normal counterpart of CLL B-cells.
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Affiliation(s)
- Walaa Darwiche
- EA 4666 Lymphocyte Normal - Pathologique et Cancers, HEMATIM, Université de Picardie Jules Verne, Amiens, France.,Laboratoire d'Hématologie, Centre Hospitalier Universitaire Amiens-Picardie, Amiens, France
| | - Brigitte Gubler
- EA 4666 Lymphocyte Normal - Pathologique et Cancers, HEMATIM, Université de Picardie Jules Verne, Amiens, France.,Laboratoire d'Oncobiologie Moléculaire, Centre Hospitalier Universitaire Amiens-Picardie, Amiens, France
| | - Jean-Pierre Marolleau
- EA 4666 Lymphocyte Normal - Pathologique et Cancers, HEMATIM, Université de Picardie Jules Verne, Amiens, France.,Service d'Hématologie Clinique et Thérapie cellulaire, Centre Hospitalier Universitaire Amiens-Picardie, Amiens, France
| | - Hussein Ghamlouch
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1170, Gustave Roussy, Villejuif, France.,Institut Gustave Roussy, Villejuif, France.,Université Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France
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10
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Alharbi RA, Pandha HS, Simpson GR, Pettengell R, Poterlowicz K, Thompson A, Harrington K, El-Tanani M, Morgan R. Inhibition of HOX/PBX dimer formation leads to necroptosis in acute myeloid leukemia cells. Oncotarget 2017; 8:89566-89579. [PMID: 29163771 PMCID: PMC5685692 DOI: 10.18632/oncotarget.20023] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 06/26/2017] [Indexed: 12/31/2022] Open
Abstract
The HOX genes encode a family of transcription factors that have key roles in both development and malignancy. Disrupting the interaction between HOX proteins and their binding partner, PBX, has been shown to cause apoptotic cell death in a range of solid tumors. However, despite HOX proteins playing a particularly significant role in acute myeloid leukemia (AML), the relationship between HOX gene expression and patient survival has not been evaluated (with the exception of HOXA9), and the mechanism by which HOX/PBX inhibition induces cell death in this malignancy is not well understood. In this study, we show that the expression of HOXA5, HOXB2, HOXB4, HOXB9, and HOXC9, but not HOXA9, in primary AML samples is significantly related to survival. Furthermore, the previously described inhibitor of HOX/PBX dimerization, HXR9, is cytotoxic to both AML-derived cell lines and primary AML cells from patients. The mechanism of cell death is not dependent on apoptosis but instead involves a regulated form of necrosis referred to as necroptosis. HXR9-induced necroptosis is enhanced by inhibitors of protein kinase C (PKC) signaling, and HXR9 combined with the PKC inhibitor Ro31 causes a significantly greater reduction in tumor growth compared to either reagent alone.
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Affiliation(s)
- Raed A. Alharbi
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha, Saudi Arabia
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | - Hardev S. Pandha
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | - Guy R. Simpson
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | | | | | - Alexander Thompson
- Division of Cancer and Stem Cells, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK
| | - Kevin Harrington
- Targeted Therapy Team, Chester Beatty Laboratories, Institute of Cancer Research, London, UK
| | - Mohamed El-Tanani
- Institute of Cancer Therapeutics, University of Bradford, Bradford, UK
| | - Richard Morgan
- Institute of Cancer Therapeutics, University of Bradford, Bradford, UK
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STAT3 mediates C6-ceramide-induced cell death in chronic lymphocytic leukemia. Signal Transduct Target Ther 2017; 2:17051. [PMID: 29263930 PMCID: PMC5661641 DOI: 10.1038/sigtrans.2017.51] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Revised: 06/09/2017] [Accepted: 08/16/2017] [Indexed: 12/24/2022] Open
Abstract
The pathogenesis of chronic lymphocytic leukemia (CLL) is poorly understood and it remains incurable with current therapies. We have previously shown that nanoliposomal C6-ceramide (CNL) is an effective therapy in an in vivo murine model of CLL. However, the key signaling pathways mediating CNL-induced cell death in CLL remains unknown. We hypothesized that CNL targets STAT3, a critical regulator of hematopoietic biology. We observed that CNL treatment reduced phosphorylated STAT3 at both Y705 and S727 residues in CLL cell lines and patient cells. This, in turn, reduced STAT3 transcriptional activity and expression of critical STAT3-dependent survival factors like Mcl-1 and survivin. The effect of CNL on STAT3 was further confirmed ex vivo as shown by reduced STAT3 phosphorylation in xenograft tumors obtained from mice treated with CNL. CNL suppressed STAT3 phosphorylation at Y705 and S727 through reduction in BTK activity and MEK1/2 kinase/PKC activities, respectively. Moreover, a synergistic reduction in CLL cell viability was observed on co-treatment with CNL and the BTK inhibitor, ibrutinib. Expression of an oncogenic form of STAT3 conferred partial resistance to CNL, providing confirmation that STAT3 mediates CNL-induced cell death. Taken together, these findings provide the first body of evidence demonstrating ceramide regulation of STAT3 phosphorylation. These results are also the first to demonstrate an effect of ceramide on BTK, a critical kinase mediating the B-cell receptor signaling in CLL cells and suggest a novel and synergistic combination of CNL and BTK inhibitors for CLL treatment.
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12
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Wang P, Lu P, Qu X, Shen Y, Zeng H, Zhu X, Zhu Y, Li X, Wu H, Xu J, Lu H, Ma Z, Zhu H. Reactivation of HIV-1 from Latency by an Ingenol Derivative from Euphorbia Kansui. Sci Rep 2017; 7:9451. [PMID: 28842560 PMCID: PMC5573388 DOI: 10.1038/s41598-017-07157-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 06/23/2017] [Indexed: 02/07/2023] Open
Abstract
Cells harboring latent HIV-1 pose a major obstacle to eradication of the virus. The ‘shock and kill’ strategy has been broadly explored to purge the latent reservoir; however, none of the current latency-reversing agents (LRAs) can safely and effectively activate the latent virus in patients. In this study, we report an ingenol derivative called EK-16A, isolated from the traditional Chinese medicinal herb Euphorbia kansui, which displays great potential in reactivating latent HIV-1. A comparison of the doses used to measure the potency indicated EK-16A to be 200-fold more potent than prostratin in reactivating HIV-1 from latently infected cell lines. EK-16A also outperformed prostratin in ex vivo studies on cells from HIV-1-infected individuals, while maintaining minimal cytotoxicity effects on cell viability and T cell activation. Furthermore, EK-16A exhibited synergy with other LRAs in reactivating latent HIV-1. Mechanistic studies indicated EK-16A to be a PKCγ activator, which promoted both HIV-1 transcription initiation by NF-κB and elongation by P-TEFb signal pathways. Further investigations aimed to add this compound to the therapeutic arsenal for HIV-1 eradication are in the pipeline.
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Affiliation(s)
- Pengfei Wang
- State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Panpan Lu
- State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Xiying Qu
- State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Yinzhong Shen
- Department of Infectious Diseases, and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200433, China
| | - Hanxian Zeng
- State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Xiaoli Zhu
- State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Yuqi Zhu
- State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Xian Li
- State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Hao Wu
- Center for Infectious Diseases, Beijing You'an Hospital, Capital Medical University, Beijing, 100069, China
| | - Jianqing Xu
- Department of Infectious Diseases, and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200433, China
| | - Hongzhou Lu
- Department of Infectious Diseases, and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200433, China
| | - Zhongjun Ma
- Institute of Marine Biology, Ocean College, Zhejiang University, Hangzhou, 310058, China.
| | - Huanzhang Zhu
- State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 200438, China.
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13
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Chen BY, Chen D, Lyu JX, Li KQ, Jiang MM, Zeng JJ, He XJ, Hao K, Tao HQ, Mou XZ, Ying YM, Zhang W, Zhu MH, Wang Z. Marsdeniae tenacissimae extract (MTE) suppresses cell proliferation by attenuating VEGF/VEGFR2 interactions and promotes apoptosis through regulating PKC pathway in human umbilical vein endothelial cells. Chin J Nat Med 2017; 14:922-930. [PMID: 28262119 DOI: 10.1016/s1875-5364(17)30017-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Indexed: 01/13/2023]
Abstract
Marsdeniae tenacissimae extract (MTE), commonly known as Xiao-Ai-Ping in China, is a traditional Chinese herb medicine capable of inhibiting proliferation and metastasis and boosting apoptosis in various cancer cells. However, little is known about the contribution of MTE towards tumor angiogenesis and the underlying mechanism. The present study aimed to evaluate the effects of MTE on the proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs) and the molecular mechanism. 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium, inner salt (MTS) and PI-stained flow cytometry assays revealed that MTE dose-dependently reduced the proliferation of HUVECs by arresting cell cycle at S phase (P < 0.05). Annexin V-FITC/PI-stained flow cytometry confirmed that MTE (160 μL·L-1) enhanced the apoptosis of HUVECs significantly (P < 0.001). Real-time quantitative RT-PCR and Western blot analyses showed an increase in Bax expression and a sharply decline in Bcl-2 expression; caspase-3 was activated simultaneously in a dose-dependent manner (P < 0.05). Further study observed the dose-dependent down-regulation of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2), P2Y6 receptor (P2Y6R), and chemokine (C-C motif) ligand 2 (CCL-2), along with the activation of PKC Δ and up-regulation of p53 in a dose-dependent manner in MTE-treated selected cells (P < 0.05). Collectively, the results from the present study suggested that MTE suppressed the proliferation by attenuating CCL-2-mediated VEGF/VEGFR2 interactions and promoted the apoptosis through PKCΔ-induced p53-dependent mitochondrial pathway in HUVECs, supporting that MTE may be developed as a potent anti-cancer medicine.
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Affiliation(s)
- Bing-Yu Chen
- Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, Hangzhou, 310014, China; Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
| | - Dong Chen
- Wenzhou Center for Disease Control and Prevention, Wenzhou 325001, China
| | - Jian-Xin Lyu
- Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, Hangzhou, 310014, China; School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou 325000, China
| | - Kai-Qiang Li
- Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, Hangzhou, 310014, China; Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
| | - Meng-Meng Jiang
- Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, Hangzhou, 310014, China; School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou 325000, China
| | - Jing-Jing Zeng
- Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, Hangzhou, 310014, China; School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou 325000, China
| | - Xu-Jun He
- Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
| | - Ke Hao
- Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, Hangzhou, 310014, China; Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
| | - Hou-Quan Tao
- Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, Hangzhou, 310014, China; Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
| | - Xiao-Zhou Mou
- Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
| | - You-Min Ying
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
| | - Wei Zhang
- Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, Hangzhou, 310014, China; Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
| | - Meng-Hua Zhu
- Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, Hangzhou, 310014, China.
| | - Zhen Wang
- Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, Hangzhou, 310014, China; School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou 325000, China.
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14
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Thurgood LA, Chataway TK, Lower KM, Kuss BJ. From genome to proteome: Looking beyond DNA and RNA in chronic lymphocytic leukemia. J Proteomics 2017; 155:73-84. [PMID: 28069558 DOI: 10.1016/j.jprot.2017.01.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 11/11/2016] [Accepted: 01/03/2017] [Indexed: 02/07/2023]
Abstract
Chronic lymphocytic leukemia (CLL) remains the most common leukemia in the Western world. Whilst its disease course is extremely heterogeneous (ranging from indolent to aggressive), current methods are unable to accurately predict the clinical journey of each patient. There is clearly a pressing need for both improved prognostication and treatment options for patients with this disease. Whilst molecular studies have analyzed both genetic mutations and gene expression profiles of these malignant B-cells, and as a result have shed light on the pathogenesis of CLL, proteomic studies have been largely overlooked to date. This review summarizes our current knowledge of the proteomics of CLL, and discusses some of the issues in CLL proteomic research, such as reproducibility and data interpretation. In addition, we look ahead to how proteomics may significantly help in the development of a successful treatment for this currently incurable disease.
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Affiliation(s)
- Lauren A Thurgood
- Department of Haematology and Genetic Pathology, Flinders University, Adelaide, South Australia, Australia.
| | - Tim K Chataway
- Department of Physiology, Flinders University, Adelaide, South Australia, Australia
| | - Karen M Lower
- Department of Haematology and Genetic Pathology, Flinders University, Adelaide, South Australia, Australia
| | - Bryone J Kuss
- Department of Haematology and Genetic Pathology, Flinders University, Adelaide, South Australia, Australia
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15
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Lei J, Li Q, Gao Y, Zhao L, Liu Y. Increased PKCα activity by Rack1 overexpression is responsible for chemotherapy resistance in T-cell acute lymphoblastic leukemia-derived cell line. Sci Rep 2016; 6:33717. [PMID: 27644318 PMCID: PMC5028770 DOI: 10.1038/srep33717] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 08/31/2016] [Indexed: 12/03/2022] Open
Abstract
Chemoresistant mechanisms in T-cell acute lymphoblastic leukemia (T-ALL) patients are not clarified. The apoptotic signaling mediated by receptor of activated C kinase 1 (Rack1), protein kinase C (PKC) and FEM1 homolog b (FEM1b) was investigated in two T-ALL-derived cell lines (Jurkat and CCRF-CEM) following treatment with chemotherapy drugs vincristine and prednisone. Serum starvation or chemotherapeutic drugs significantly reduced Rack1 level and PKC activation, while promoted cellular apoptosis in both cell lines. Rack1 overexpression protected T-ALL cell against starvation or chemotherapeutic drug-induced apoptosis. Moreover, Rack1 overexpression reduced the level of cytochrome c and active caspase 3 as well as FEM1b and apoptotic protease activating factor-1 (Apaf-1), and inhibited induction of cellular apoptosis in chemotherapeutic drug-treated Jurkat cell. Interaction of Rack1 and PKCα, not PKCβ, was detected in both cell lines. Of note, Rack1 overexpression abrogated reduction of PKC kinase activity in chemotherapeutic drug-treated T-ALL cell. PKC kinase inhibitor Go6976 or siPKCα inhibited downregulation of FEM1b and/or Apaf-1, and thus increased cellular apoptosis in Rack1-overexpressed T-ALL cell receiving chemotherapeutic drugs. Accordingly, our data provided evidence that increased Rack1-mediated upregulation of PKC kinase activity may be responsible for the development of chemoresistance in T-ALL-derived cell line potentially by reducing FEM1b and Apaf-1 level.
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Affiliation(s)
- Jie Lei
- Department of Pediatrics, First Hospital of Jilin University, Changchun, Jilin, PR China
| | - Qi Li
- Department of Pediatrics, First Hospital of Jilin University, Changchun, Jilin, PR China
| | - Ying Gao
- Department of Pediatrics, People's Hospital of Shaanxi Province, Shaanxi, XiAn, PR China
| | - Lei Zhao
- Department of Pediatrics, First Hospital of Jilin University, Changchun, Jilin, PR China
| | - Yanbo Liu
- Department of Pediatrics, First Hospital of Jilin University, Changchun, Jilin, PR China
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16
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Metformin Induces Cell Cycle Arrest and Apoptosis in Drug-Resistant Leukemia Cells. LEUKEMIA RESEARCH AND TREATMENT 2015; 2015:516460. [PMID: 26688757 PMCID: PMC4673355 DOI: 10.1155/2015/516460] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 06/18/2015] [Accepted: 09/20/2015] [Indexed: 12/25/2022]
Abstract
Recent epidemiological studies indicate that the antidiabetic drug metformin has chemosensitizing and chemopreventive effects against carcinogenesis. Here, we demonstrate that metformin exerts varying degrees of antitumor activity against human leukemia cells, as reflected by differences in growth inhibition, apoptosis, and alterations to metabolic enzymes. In metformin-sensitive cells, autophagy was not induced but rather it blocked proliferation by means of arresting cells in the S and G2/M phases which was associated with the downregulation of cyclin A, cyclin B1, and cdc2, but not that of cyclin E. In 10E1-CEM cells that overexpress Bcl-2 and are drug-resistant, the effect of metformin on proliferation was more pronounced, also inducing the activation of the caspases 3/7 and hence apoptosis. In all sensitive cells, metformin decreased the Δψm and it modified the expression of enzymes involved in energy metabolism: PKCε (PKCepsilon) and PKCδ (PKCdelta). In sensitive cells, metformin altered PKCε and PKCδ expression leading to a predominance of PKCε over PKCδ which implies a more glycolytic state. The opposite occurs in the nonresponsive cells. In conclusion, we provide new insights into the activity of metformin as an antitumoral agent in leukemia cells that could be related to its capability to modulate energy metabolism.
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17
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Kazi JU, Kabir NN, Rönnstrand L. Brain-Expressed X-linked (BEX) proteins in human cancers. Biochim Biophys Acta Rev Cancer 2015; 1856:226-33. [PMID: 26408910 DOI: 10.1016/j.bbcan.2015.09.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 09/20/2015] [Accepted: 09/22/2015] [Indexed: 01/08/2023]
Abstract
The Brain-Expressed X-linked (BEX) family proteins are comprised of five human proteins including BEX1, BEX2, BEX3, BEX4 and BEX5. BEX family proteins are expressed in a wide range of tissues and are known to play a role in neuronal development. Recent studies suggest a role of BEX family proteins in cancers. BEX1 expression is lost in a subgroup of patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Expression of BEX1 controls cell surface receptor signaling and restores imatinib response in resistant cells. BEX2 is overexpressed in a group of breast cancer patients and also in gliomas. Increased BEX2 expression led to enhanced NF-κB signaling as well as cell proliferation. Although BEX2 acts as tumor promoter in a subset of breast cancer, BEX3 expression displayed an opposite role. Overexpression of BEX3 resulted in inhibition of tumor formation in breast cancer mouse xenograft models. The role of BEX4 and BEX5 in cancer has not yet been defined. Collectively this suggests that BEX family members have distinct roles in cancers. While BEX1 and BEX3 act as tumor suppressors, BEX2 seems to act as an oncogene.
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Affiliation(s)
- Julhash U Kazi
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village 404 ,Lund, Sweden; Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden; Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal, Bangladesh.
| | - Nuzhat N Kabir
- Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal, Bangladesh
| | - Lars Rönnstrand
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village 404 ,Lund, Sweden; Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
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18
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Crassini K, Mulligan SP, Best OG. Targeting chronic lymphocytic leukemia cells in the tumor microenviroment: A review of the in vitro and clinical trials to date. World J Clin Cases 2015; 3:694-704. [PMID: 26301230 PMCID: PMC4539409 DOI: 10.12998/wjcc.v3.i8.694] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 12/23/2014] [Accepted: 06/04/2015] [Indexed: 02/05/2023] Open
Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. Despite significant advances in therapy over the last decade CLL remains incurable. Current front-line therapy often consists of chemoimmunotherapy-based regimens, most commonly the fludarabine, cyclophosphamide plus rituximab combination, but rates of relapse and refractory disease are high among these patients. Several key signaling pathways are now known to mediate the survival and proliferation of CLL cells in vivo, the most notable of which are the pathways mediated by the B-cell receptor (BCR) and cytokine receptors. A better understanding of the pathogenesis of the disease, the underlying biology of the CLL-cell and the roles of the tumour microenvironment has provided the rationale for trials of a range of novel, more targeted therapeutic agents. In particular, clinical trials of ibrutinib and idelalisib, which target the Brutons tyrosine kinase and the delta isoform of phosphoinositol-3 kinase components of the BCR signaling pathway respectively, have shown extremely promising results. Here we review the current literature on the key signaling pathways and interactions of CLL cells that mediate the survival and proliferation of the leukemic cells. For each we describe the results of the recent clinical trials and in vitro studies of novel therapeutic agents.
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Kazi JU, Kabir NN, Rönnstrand L. Role of SRC-like adaptor protein (SLAP) in immune and malignant cell signaling. Cell Mol Life Sci 2015; 72:2535-44. [PMID: 25772501 PMCID: PMC11113356 DOI: 10.1007/s00018-015-1882-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 03/01/2015] [Accepted: 03/05/2015] [Indexed: 01/05/2023]
Abstract
SRC-like adaptor protein (SLAP) is an adaptor protein structurally similar to the SRC family protein kinases. Like SRC, SLAP contains an SH3 domain followed by an SH2 domain but the kinase domain has been replaced by a unique C-terminal region. SLAP is expressed in a variety of cell types. Current studies suggest that it regulates signaling of various cell surface receptors including the B cell receptor, the T cell receptor, cytokine receptors and receptor tyrosine kinases which are important regulator of immune and cancer cell signaling. SLAP targets receptors, or its associated components, by recruiting the ubiquitin machinery and thereby destabilizing signaling. SLAP directs receptors to ubiquitination-mediated degradation and controls receptors turnover as well as signaling. Thus, SLAP appears to be an important component in regulating signal transduction required for immune and malignant cells.
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Affiliation(s)
- Julhash U. Kazi
- Division of Translational Cancer Research, Lund University, Medicon Village 404:C3, 223 63 Lund, Sweden
- Lund Stem Cell Center, Lund University, Lund, Sweden
- Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal, Bangladesh
| | - Nuzhat N. Kabir
- Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal, Bangladesh
| | - Lars Rönnstrand
- Division of Translational Cancer Research, Lund University, Medicon Village 404:C3, 223 63 Lund, Sweden
- Lund Stem Cell Center, Lund University, Lund, Sweden
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20
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Corsini E, Galbiati V, Pinto A, Davin A, Polito L, Guaita A, Racchi M. Immunostimulatory effects of RACK1 pseudosubstrate in human leukocytes obtained from young and old donors. Oncotarget 2015; 6:6524-34. [PMID: 25779661 PMCID: PMC4466631 DOI: 10.18632/oncotarget.3002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 12/21/2014] [Indexed: 11/25/2022] Open
Abstract
Aims of this study were to investigate the ability of RACK1 pseudosubstrate alone or in combination with classical immune stimuli to activate human leukocytes, and to restore age-associated immune defects.A total of 25 donors (17 old donors, 77-79 yrs; 8 young donors, 25-34 yrs) were enrolled. To evaluate the effect of RACK1 pseudosubstrate on cytokine production and CD86 expression the whole blood assay was used. Cultures were treated with RACK1 pseudosubstrate in the presence or absence of lipopolysaccharide (LPS) or phytohaemagglutinin (PHA) and incubated for 24 h or 48 h for LPS-induced CD86 expression, TNF-α, IL-6, IL-8, IL-10 production, and PHA-induced IL-4, IL-10, IFN-γ, respectively. RACK1 pseudosubstrate alone induced IL-6, IL-8, and CD86 expression in both young and old donors, and IFN-γ in old donors. In combination with LPS an increase in IL-8, IL-10 and TNF-α was observed, also resulting in restoration of age-associated defective production, while no changes in the other parameters investigated were found.Even if based on a small sample size, these results suggest the possibility to by-pass some of age-associated immune alterations, which may be beneficial in situations were natural immune stimulation is required, and highlight a different role of PKCβ in immune cells activation.
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Affiliation(s)
- Emanuela Corsini
- Laboratory of Toxicology, DiSFeB, Università degli Studi di Milano, Milan, Italy
| | - Valentina Galbiati
- Laboratory of Toxicology, DiSFeB, Università degli Studi di Milano, Milan, Italy
| | - Antonella Pinto
- Department of Drug Sciences - Pharmacology, University of Pavia, Pavia, Italy
| | | | | | | | - Marco Racchi
- Department of Drug Sciences - Pharmacology, University of Pavia, Pavia, Italy
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21
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Kazi JU, Kabir NN, Flores-Morales A, Rönnstrand L. SOCS proteins in regulation of receptor tyrosine kinase signaling. Cell Mol Life Sci 2014; 71:3297-310. [PMID: 24705897 PMCID: PMC11113172 DOI: 10.1007/s00018-014-1619-y] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 03/12/2014] [Accepted: 03/21/2014] [Indexed: 12/17/2022]
Abstract
Receptor tyrosine kinases (RTKs) are a family of cell surface receptors that play critical roles in signal transduction from extracellular stimuli. Many in this family of kinases are overexpressed or mutated in human malignancies and thus became an attractive drug target for cancer treatment. The signaling mediated by RTKs must be tightly regulated by interacting proteins including protein-tyrosine phosphatases and ubiquitin ligases. The suppressors of cytokine signaling (SOCS) family proteins are well-known negative regulators of cytokine receptors signaling consisting of eight structurally similar proteins, SOCS1-7, and cytokine-inducible SH2-containing protein (CIS). A key feature of this family of proteins is the presence of an SH2 domain and a SOCS box. Recent studies suggest that SOCS proteins also play a role in RTK signaling. Activation of RTK results in transcriptional activation of SOCS-encoding genes. These proteins associate with RTKs through their SH2 domains and subsequently recruit the E3 ubiquitin machinery through the SOCS box, and thereby limit receptor stability by inducing ubiquitination. In a similar fashion, SOCS proteins negatively regulate mitogenic signaling by RTKs. It is also evident that RTKs can sometimes bypass SOCS regulation and SOCS proteins can even potentiate RTKs-mediated mitogenic signaling. Thus, apart from negative regulation of receptor signaling, SOCS proteins may also influence signaling in other ways.
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Affiliation(s)
- Julhash U. Kazi
- Division of Translational Cancer Research, Lund University, Medicon Village, Lund, Sweden
- Lund Stem Cell Center, Lund University, Lund, Sweden
- Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal, Bangladesh
| | - Nuzhat N. Kabir
- Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal, Bangladesh
| | - Amilcar Flores-Morales
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lars Rönnstrand
- Division of Translational Cancer Research, Lund University, Medicon Village, Lund, Sweden
- Lund Stem Cell Center, Lund University, Lund, Sweden
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22
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Kabir NN, Sun J, Rönnstrand L, Kazi JU. SOCS6 is a selective suppressor of receptor tyrosine kinase signaling. Tumour Biol 2014; 35:10581-9. [PMID: 25172101 DOI: 10.1007/s13277-014-2542-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 08/21/2014] [Indexed: 01/17/2023] Open
Abstract
The suppressors of cytokine signaling (SOCS) are well-known negative regulators of cytokine receptor signaling. SOCS6 is one of eight members of the SOCS family of proteins. Similar to other SOCS proteins, SOCS6 consists of an uncharacterized extended N-terminal region followed by an SH2 domain and a SOCS box. Unlike other SOCS proteins, SOCS6 is mainly involved in negative regulation of receptor tyrosine kinase signaling. SOCS6 is widely expressed in many tissues and is found to be downregulated in many cancers including colorectal cancer, gastric cancer, lung cancer, ovarian cancer, stomach cancer, thyroid cancer, hepatocellular carcinoma, and pancreatic cancer. SOCS6 is involved in negative regulation of receptor signaling by increasing degradation mediated by ubiquitination of receptors or substrate proteins and induces apoptosis by targeting mitochondrial proteins. Therefore, SOCS6 turns out as an important regulator of survival signaling and its activity is required for controlling receptor tyrosine kinase signaling.
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Affiliation(s)
- Nuzhat N Kabir
- Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal, Bangladesh
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23
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Mencalha AL, Corrêa S, Abdelhay E. Role of calcium-dependent protein kinases in chronic myeloid leukemia: combined effects of PKC and BCR-ABL signaling on cellular alterations during leukemia development. Onco Targets Ther 2014; 7:1247-54. [PMID: 25045273 PMCID: PMC4099416 DOI: 10.2147/ott.s64303] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Calcium-dependent protein kinases (PKCs) function in a myriad of cellular processes, including cell-cycle regulation, proliferation, hematopoietic stem cell differentiation, apoptosis, and malignant transformation. PKC inhibitors, when targeted to these pathways, have demonstrated efficacy against several types of solid tumors as well as leukemia. Chronic myeloid leukemia (CML) represents 20% of all adult leukemia. The aberrant Philadelphia chromosome has been reported as the main cause of CML development in hematopoietic stem cells, due to the formation of the BCR-ABL oncogene. PKCs and BCR-ABL coordinate several signaling pathways that are crucial to cellular malignant transformation. Experimental and clinical evidence suggests that pharmacological approaches using PKC inhibitors may be effective in the treatment of CML. This mini review summarizes articles from the National Center for Biotechnology Information website that have shown evidence of the involvement of PKC in CML.
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Affiliation(s)
- André L Mencalha
- Biophysics and Biometry Department, Roberto Alcântara Gomes Biology Institute, Rio de Janeiro's State University (UERJ), Rio de Janeiro, Brazil
| | - Stephany Corrêa
- Bone Marrow Transplantation Unit (CEMO), National Cancer Institute (INCA), Rio de Janeiro, Brazil
| | - Eliana Abdelhay
- Bone Marrow Transplantation Unit (CEMO), National Cancer Institute (INCA), Rio de Janeiro, Brazil
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24
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Abstract
Copper is an essential element in many biological processes. The critical functions associated with copper have resulted from evolutionary harnessing of its potent redox activity. This same property also places copper in a unique role as a key modulator of cell signal transduction pathways. These pathways are the complex sequence of molecular interactions that drive all cellular mechanisms and are often associated with the interplay of key enzymes including kinases and phosphatases but also including intracellular changes in pools of smaller molecules. A growing body of evidence is beginning to delineate the how, when and where of copper-mediated control over cell signal transduction. This has been driven by research demonstrating critical changes to copper homeostasis in many disorders including cancer and neurodegeneration and therapeutic potential through control of disease-associated cell signalling changes by modulation of copper-protein interactions. This timely review brings together for the first time the diverse actions of copper as a key regulator of cell signalling pathways and discusses the potential strategies for controlling disease-associated signalling processes using copper modulators. It is hoped that this review will provide a valuable insight into copper as a key signal regulator and stimulate further research to promote our understanding of copper in disease and therapy.
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Ghamlouch H, Ouled-Haddou H, Guyart A, Regnier A, Trudel S, Claisse JF, Fuentes V, Royer B, Marolleau JP, Gubler B. Phorbol myristate acetate, but not CD40L, induces the differentiation of CLL B cells into Ab-secreting cells. Immunol Cell Biol 2014; 92:591-604. [PMID: 24797583 PMCID: PMC4134517 DOI: 10.1038/icb.2014.37] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 03/21/2014] [Accepted: 03/24/2014] [Indexed: 11/29/2022]
Abstract
In this study, we investigated the capacity of chronic lymphocytic leukemia (CLL) B cells to undergo terminal differentiation into Ig-secreting plasma cells in T cell-independent and T cell-dependent responses. We used a two-step model involving stimulation with phorbol myristate acetate (PMA) and CD40L, together with cytokines (PMA/c and CD40L/c), for 7 days. We describe immunophenotypic modifications, changes in the levels of mRNA and protein for transcription factors and morphological and functional events occurring during the differentiation of CLL B cells into antibody-secreting cells (ASCs). The induction of differentiation differed significantly between the CD40L/c and PMA/c culture systems. The PMA/c culture system allowed CLL B cells to differentiate into IgM-secreting cells with an immunophenotype and molecular profile resembling those of preplasmablasts. By contrast, CD40L/c-stimulated cells had a phenotype and morphology similar to those of activated B cells and resembling those of the CLL B cells residing in the lymph node and bone marrow. These data suggest that the CLL B cells are not frozen permanently at a stage of differentiation and are able to differentiate into ASCs as appropriate stimulation are provided. The data presented here raise questions about the molecular processes and stimulation required for CLL B-cell differentiation and about the inability of CD40 ligand to induce differentiation of the CLL B cells.
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Affiliation(s)
- Hussein Ghamlouch
- EA4666, Laboratoire d'Immunologie, UFR de Médecine, Université de Picardie Jules Verne, Amiens, France
| | - Hakim Ouled-Haddou
- EA4666, Laboratoire d'Immunologie, UFR de Médecine, Université de Picardie Jules Verne, Amiens, France
| | - Aude Guyart
- EA4666, Laboratoire d'Immunologie, UFR de Médecine, Université de Picardie Jules Verne, Amiens, France
| | - Aline Regnier
- 1] EA4666, Laboratoire d'Immunologie, UFR de Médecine, Université de Picardie Jules Verne, Amiens, France [2] Service d'Hématologie Clinique et Thérapie Cellulaire, CHU d'Amiens, Avenue René Laënnec, Amiens, France
| | - Stéphanie Trudel
- 1] EA4666, Laboratoire d'Immunologie, UFR de Médecine, Université de Picardie Jules Verne, Amiens, France [2] Laboratoire d'Oncobiologie Moléculaire, CHU d'Amiens, Avenue René Laënnec, Amiens, France
| | - Jean-François Claisse
- Service d'Hématologie Clinique et Thérapie Cellulaire, CHU d'Amiens, Avenue René Laënnec, Amiens, France
| | - Vincent Fuentes
- EA4666, Laboratoire d'Immunologie, UFR de Médecine, Université de Picardie Jules Verne, Amiens, France
| | - Bruno Royer
- 1] EA4666, Laboratoire d'Immunologie, UFR de Médecine, Université de Picardie Jules Verne, Amiens, France [2] Service d'Hématologie Clinique et Thérapie Cellulaire, CHU d'Amiens, Avenue René Laënnec, Amiens, France
| | - Jean-Pierre Marolleau
- 1] EA4666, Laboratoire d'Immunologie, UFR de Médecine, Université de Picardie Jules Verne, Amiens, France [2] Service d'Hématologie Clinique et Thérapie Cellulaire, CHU d'Amiens, Avenue René Laënnec, Amiens, France
| | - Brigitte Gubler
- 1] EA4666, Laboratoire d'Immunologie, UFR de Médecine, Université de Picardie Jules Verne, Amiens, France [2] Laboratoire d'Oncobiologie Moléculaire, CHU d'Amiens, Avenue René Laënnec, Amiens, France
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Abstract
Protein kinase C (PKC) is a family of phospholipid-dependent serine/threonine kinases, which can be further classified into three PKC isozymes subfamilies: conventional or classic, novel or nonclassic, and atypical. PKC isozymes are known to be involved in cell proliferation, survival, invasion, migration, apoptosis, angiogenesis, and drug resistance. Because of their key roles in cell signaling, PKC isozymes also have the potential to be promising therapeutic targets for several diseases, such as cardiovascular diseases, immune and inflammatory diseases, neurological diseases, metabolic disorders, and multiple types of cancer. This review primarily focuses on the activation, mechanism, and function of PKC isozymes during cancer development and progression.
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Kabir NN, Kazi JU. Grb10 is a dual regulator of receptor tyrosine kinase signaling. Mol Biol Rep 2014; 41:1985-92. [PMID: 24420853 DOI: 10.1007/s11033-014-3046-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2013] [Accepted: 01/04/2014] [Indexed: 10/25/2022]
Abstract
The adaptor protein Grb10 is a close homolog of Grb7 and Grb14. These proteins are characterized by an N-terminal proline-rich region, a Ras-GTPase binding domain, a PH domain, an SH2 domain and a BPS domain in between the PH and SH2 domains. Human Grb10 gene encodes three splice variants. These variants show differences in functionality. Grb10 associates with multiple proteins including tyrosine kinases in a tyrosine phosphorylation dependent or independent manner. Association with multiple proteins allows Grb10 to regulate different signaling pathways resulting in different biological consequences.
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Affiliation(s)
- Nuzhat N Kabir
- Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Bagura Road, Barisal, Bangladesh
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