MiR-15a-5p Confers Chemoresistance in Acute Myeloid Leukemia by Inhibiting Autophagy Induced by Daunorubicin

Autor: Jean-Baptiste Demoulin, Melissa Claus, Emeline Bollaert, Ahmed Essaghir, Violaine Havelange, Virginie Vandewalle, Sandrine Lenglez
Přispěvatelé: UCL - SSS/DDUV/MEXP - Médecine expérimentale
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Myeloid
Apoptosis
0302 clinical medicine
hemic and lymphatic diseases
polycyclic compounds
Tumor Cells
Cultured
Biology (General)
Spectroscopy
Antibiotics
Antineoplastic
microRNA
Myeloid leukemia
chemoresistance
General Medicine
Computer Science Applications
Gene Expression Regulation
Neoplastic
Chemistry
Leukemia
Myeloid
Acute
medicine.anatomical_structure
030220 oncology & carcinogenesis
medicine.drug
Adult
autophagy
Daunorubicin
QH301-705.5
acute myeloid leukemia
Catalysis
Article
Inorganic Chemistry
03 medical and health sciences
Downregulation and upregulation
medicine
Biomarkers
Tumor
Humans
Physical and Theoretical Chemistry
Molecular Biology
QD1-999
neoplasms
Cell Proliferation
business.industry
Gene Expression Profiling
Organic Chemistry
Autophagy
target genes
carbohydrates (lipids)
MicroRNAs
030104 developmental biology
daunorubicin
Drug Resistance
Neoplasm
Cancer research
Cytarabine
business
Zdroj: International Journal of Molecular Sciences
Volume 22
Issue 10
International journal of molecular sciences, Vol. 22, no.10, p. 5153 (2021)
International Journal of Molecular Sciences, Vol 22, Iss 5153, p 5153 (2021)
ISSN: 1422-0067
DOI: 10.3390/ijms22105153
Popis: Anthracyclines remain a cornerstone of induction chemotherapy for acute myeloid leukemia (AML). Refractory or relapsed disease due to chemotherapy resistance is a major obstacle in AML management. MicroRNAs (miRNAs) have been observed to be involved in chemoresistance. We previously observed that miR-15a-5p was overexpressed in a subgroup of chemoresistant cytogenetically normal AML patients compared with chemosensitive patients treated with daunorubicin and cytarabine. MiR-15a-5p overexpression in AML cells reduced apoptosis induced by both drugs in vitro. This study aimed to elucidate the mechanisms by which miR-15a-5p contributes to daunorubicin resistance. We showed that daunorubicin induced autophagy in myeloid cell lines. The inhibition of autophagy reduced cell sensitivity to daunorubicin. The overexpression of miR-15a-5p decreased daunorubicin-induced autophagy. Conversely, the downregulation of miR-15a-5p increased daunorubicin-induced autophagy. We found that miR-15a-5p targeted four genes involved in autophagy, namely ATG9a, ATG14, GABARAPL1 and SMPD1. Daunorubicin increased the expression of these four genes, and miR-15a-5p counteracted this regulation. Inhibition experiments with the four target genes showed the functional effect of miR-15a-5p on autophagy. In summary, our results indicated that miR-15a-5p induces chemoresistance in AML cells through the abrogation of daunorubicin-induced autophagy, suggesting that miR-15a-5p could be a promising therapeutic target for chemoresistant AML patients.
Databáze: OpenAIRE
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