Idarubicin induces mTOR-dependent cytotoxic autophagy in leukemic cells
| Autor: | Violeta Suzin-Zivkovic, Aleksandar Mirčić, Vladimir Perovic, Andrija Bogdanovic, Tamara Martinovic, Vladimir Trajkovic, Vladimir Bumbasirevic, Biljana Ristic, Katarina Arsikin, Tamara Kravic-Stevovic, Mihajlo Bosnjak, Ljubica Harhaji-Trajkovic |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Apoptosis Biology Immunoenzyme Techniques Leukemia Myelogenous Chronic BCR-ABL Positive Autophagy Tumor Cells Cultured medicine Humans Idarubicin Lymphocytes Phosphorylation Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Membrane Potential Mitochondrial Antibiotics Antineoplastic Cell growth TOR Serine-Threonine Kinases RPTOR Membrane Proteins Cell Biology Precursor Cell Lymphoblastic Leukemia-Lymphoma 3. Good health Cell biology Microscopy Fluorescence Microscopy Electron Scanning Cancer research Beclin-1 Apoptosis Regulatory Proteins Proto-Oncogene Proteins c-akt Signal Transduction medicine.drug K562 cells |
| Zdroj: | Experimental Cell Research. 326:90-102 |
| ISSN: | 0014-4827 |
| Popis: | We investigated if the antileukemic drug idarubicin induces autophagy, a process of programmed cellular self-digestion, in leukemic cell lines and primary leukemic cells. Transmission electron microscopy and acridine orange staining demonstrated the presence of autophagic vesicles and intracellular acidification, respectively, in idarubicin-treated REH leukemic cell line. Idarubicin increased punctuation/aggregation of microtubule-associated light chain 3B (LC3B), enhanced the conversion of LC3B-I to autophagosome-associated LC3B-II in the presence of proteolysis inhibitors, and promoted the degradation of the selective autophagic target p62, thus indicating the increase in autophagic flux. Idarubicin inhibited the phosphorylation of the main autophagy repressor mammalian target of rapamycin (mTOR) and its downstream target p70S6 kinase. The treatment with the mTOR activator leucine prevented idarubicin-mediated autophagy induction. Idarubicin-induced mTOR repression was associated with the activation of the mTOR inhibitor AMP-activated protein kinase and down-regulation of the mTOR activator Akt. The suppression of autophagy by pharmacological inhibitors or LC3B and beclin-1 genetic knockdown rescued REH cells from idarubicin-mediated oxidative stress, mitochondrial depolarization, caspase activation and apoptotic DNA fragmentation. Idarubicin also caused mTOR inhibition and cytotoxic autophagy in K562 leukemic cell line and leukocytes from chronic myeloid leukemia patients, but not healthy controls. By demonstrating mTOR-dependent cytotoxic autophagy in idarubicin-treated leukemic cells, our results warrant caution when considering combining idarubicin with autophagy inhibitors in leukemia therapy. |
| Databáze: | OpenAIRE |
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