Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia

Autor: Malak Qattan, Leo A. H. Zeef, Vaskar Saha, Constantinos Demonacos, Jizhong Liu, Daphne Wei Chen Chen, Luciano Mutti, Jean-Marc Schwartz, Ramkumar Rajendran, Marija Krstic-Demonacos, Emyr Bakker
Rok vydání: 2017
Předmět:
0301 basic medicine
Cancer Treatment
lcsh:Medicine
Gene Expression
Apoptosis
Biochemistry
Dexamethasone
Inhibitor of Apoptosis Proteins
Hematologic Cancers and Related Disorders
Glucocorticoid receptor
Tumor Microenvironment
Medicine and Health Sciences
Topoisomerase II Inhibitors
Phosphorylation
Post-Translational Modification
lcsh:Science
Etoposide
Caspase 8
Multidisciplinary
Cell Death
Caspase 3
Hematology
Genomics
BECN1
Azocines
Baculoviral IAP Repeat-Containing 3 Protein
Gene Expression Regulation
Neoplastic
medicine.anatomical_structure
Oncology
Cell Processes
Receptor-Interacting Protein Serine-Threonine Kinases
Beclin-1
Transcriptome Analysis
Signal Transduction
Research Article
medicine.drug
Programmed cell death
Ubiquitin-Protein Ligases
Autophagic Cell Death
Antineoplastic Agents
Bone Marrow Cells
Biology
Cell Line
Necrosis
03 medical and health sciences
RIPK1
Receptors
Glucocorticoid
Cell Line
Tumor
Leukemias
Genetics
medicine
Humans
Benzhydryl Compounds
Glucocorticoids
Tumor microenvironment
lcsh:R
C441
Biology and Life Sciences
Proteins
Cancers and Neoplasms
Computational Biology
A100
Cell Biology
Genome Analysis
Molecular biology
030104 developmental biology
Drug Resistance
Neoplasm
Culture Media
Conditioned
Cancer research
lcsh:Q
Bone marrow
K562 Cells
Transcriptome
Zdroj: PLoS ONE
PloS one
PLoS ONE, Vol 12, Iss 6, p e0178606 (2017)
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0178606
Popis: Glucocorticoids (GCs) and topoisomerase II inhibitors are used to treat acute lymphoblastic leukaemia (ALL) as they induce death in lymphoid cells through the glucocorticoid receptor (GR) and p53 respectively. Mechanisms underlying ALL cell death and the contribution of the bone marrow microenvironment to drug response/resistance remain unclear. The role of the microenvironment and the identification of chemoresistance determinants were studied by transcriptomic analysis in ALL cells treated with Dexamethasone (Dex), and Etoposide (Etop) grown in the presence or absence of bone marrow conditioned media (CM). The necroptotic (RIPK1) and the apoptotic (caspase-8/3) markers were downregulated by CM, whereas the inhibitory effects of chemotherapy on the autophagy marker Beclin-1 (BECN1) were reduced suggesting CM exerts cytoprotective effects. GCs upregulated the RIPK1 ubiquitinating factor BIRC3 (cIAP2), in GC-sensitive (CEM-C7-14) but not in resistant (CEM-C1-15) cells. In addition, CM selectively affected GR phosphorylation in a site and cell-specific manner. GR is recruited to RIPK1, BECN1 and BIRC3 promoters in the sensitive but not in the resistant cells with phosphorylated GR forms being generally less recruited in the presence of hormone. FACS analysis and caspase-8 assays demonstrated that CM promoted a pro-survival trend. High molecular weight proteins reacting with the RIPK1 antibody were modified upon incubation with the BIRC3 inhibitor AT406 in CEM-C7-14 cells suggesting that they represent ubiquitinated forms of RIPK1. Our data suggest that there is a correlation between microenvironment-induced ALL proliferation and altered response to chemotherapy.
Databáze: OpenAIRE
Externí odkaz: