Hypoxia promotes chemoresistance in acute lymphoblastic leukemia cell lines by modulating death signaling pathways

Autor: C. Heuclin, C. Petit, Isabelle Dubus, J. P. Vannier, Flore Gouel, K. Roget
Přispěvatelé: Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biosims Technologies
Rok vydání: 2016
Předmět:
RPPA
0301 basic medicine
Cancer Research
Cell Survival
Prednisolone
Cell
Apoptosis
[SDV.CAN]Life Sciences [q-bio]/Cancer
Pharmacology
03 medical and health sciences
0302 clinical medicine
Cell Line
Tumor
Genetics
Humans
Medicine
Viability assay
Hypoxia
Cell growth
business.industry
[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Hypoxia (medical)
medicine.disease
Cell Hypoxia
3. Good health
Leukemia
Methotrexate
030104 developmental biology
medicine.anatomical_structure
Oncology
Drug Resistance
Neoplasm
Cell culture
030220 oncology & carcinogenesis
[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Cancer research
Signal transduction
medicine.symptom
ALL
business
Chemoresistance
Signal Transduction
Research Article
Zdroj: BMC Cancer
BMC Cancer, BioMed Central, 2016, 16, pp.746. ⟨10.1186/s12885-016-2776-1⟩
ISSN: 1471-2407
Popis: Background Several studies show that bone marrow (BM) microenvironment and hypoxia condition can promote the survival of leukemic cells and induce resistance to anti-leukemic drugs. However, the molecular mechanism for chemoresistance by hypoxia is not fully understood. Methods In the present study, we investigated the effect of hypoxia on resistance to two therapies, methotrexate (MTX) and prednisolone (PRD), in two cell models for acute lymphoblastic leukemia (ALL). To look for an implication of hypoxia in chemoresistance, cell viability, total cell density and cell proliferation were analyzed. Survival and death signaling pathways were also screened by “reverse phase protein array” (RPPA) and western blotting experiments conducted on selected proteins to confirm the results. Results We found that hypoxia promotes chemoresistance in both ALL cell lines. The induction of drug-resistance by hypoxia was not associated with an increase in total cell density nor an increase in cell proliferation. Using RPPA, we show that chemoresistance induced by hypoxia was mediated through an alteration of cell death signaling pathways. This protective effect of hypoxia seems to occur via a decrease in pro-apoptotic proteins and an increase in anti-apoptotic proteins. The results were confirmed by immunoblotting. Indeed, hypoxia is able to modulate the expression of anti-apoptotic proteins independently of chemotherapy while a pro-apoptotic signal induced by a chemotherapy is not modulated by hypoxia. Conclusions Hypoxia is a factor in leukemia cell resistance and for two conventional chemotherapies modulates cell death signaling pathways without affecting total cell density or cell proliferation. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2776-1) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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