Idarubicin induces mTOR-dependent cytotoxic autophagy in leukemic cells

Ristić, Biljana; Bošnjak, Mihajlo; Arsikin, Katarina; Mirčić, Aleksandar; Suzin-Zivkovic, Violeta; Bogdanović, Andrija; Perović, Vladimir; Martinović, Tamara; Kravić-Stevović, Tamara; Bumbaširević, Vladimir; Trajkovič, Vladimir; Harhaji-Trajković, Ljubica

doi:10.1016/j.yexcr.2014.05.021

Cited by 30 publications

(26 citation statements)

References 45 publications

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“…To demonstrate a role of autophagy in mediating OGD-induced claudin-5 degradation, we first assessed the conversion of microtubule-associated protein light chain 3B-I (LC3B-I) to LC3B-II, a well-established indicator of autophagy activation [22]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Nitric Oxide Interacts with Caveolin-1 to Facilitate Autophagy-Lysosome-Mediated Claudin-5 Degradation in Oxygen-Glucose Deprivation-Treated Endothelial Cells

et al. 2015

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Using in vitro oxygen-glucose deprivation (OGD) model, we have previously demonstrated that 2-h OGD induces rapid, caveolin-1-mediated dissociation of claudin-5 from the cellular cytoskeletal framework and quick endothelial barrier disruption. In this study, we further investigated the fate of translocated claudin-5 and the mechanisms by which OGD promotes caveolin-1 translocation. Exposure of bEND3 cells to 4-h OGD, but not 2-h OGD plus 2-h reoxygenation, resulted in claudin-5 degradation. Inhibition of autophagy or the fusion of autophagosome with lysosome, but not proteasome, blocked OGD-induced claudin-5 degradation. Moreover, knockdown of caveolin-1 with siRNA blocked OGD-induced claudin-5 degradation. Western blot analysis showed a transient colocalization of caveolin-1, claudin-5, and LC3B in autolysosome or lipid raft fractions at 2-h OGD. Of note, inhibiting autophagosome and lysosome fusion sustained the colocalization of caveolin-1, claudin-5, and LC3B throughout the 4-h OGD exposure. EPR spin trapping showed increased nitric oxide (NO) generation in 2-h OGD-treated cells, and inhibiting NO with its scavenger C-PTIO or inducible nitric oxide synthase (iNOS) inhibitor 1400W prevented OGD-induced caveolin-1 translocation and claudin-5 degradation. Taken together, our data provide a novel mechanism underlying endothelial barrier disruption under prolonged ischemic conditions, in which NO promotes caveolin-1-mediated delivery of claudin-5 to the autophagosome for autophagy-lysosome-dependent degradation.

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Section: Resultsmentioning

confidence: 99%

Nitric Oxide Interacts with Caveolin-1 to Facilitate Autophagy-Lysosome-Mediated Claudin-5 Degradation in Oxygen-Glucose Deprivation-Treated Endothelial Cells

et al. 2015

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“…Autophagy was shown to contribute to both cytarabine and idarubicin's efficacy in AML cells. 39,40 Autophagy is also required for mitoxantrone-induced immunogenic signaling in tumors. 41 Moreover, arsenic trioxide, 42,43 vitamin D3, 44 vitamin K2, 45 eupalinin A (sesquiterpene lactone), 46 BAY11-7082 (NF-kB inhibitor), 47 morphinone (a morphin derivative), 48 APO866 (NAD biosynthesis inhibitor), 49 and platonin 50 have all been reported to induce leukemia cell death via activation of autophagy.…”

Section: Discussionmentioning

confidence: 99%

Caspase-3 controls AML1-ETO–driven leukemogenesis via autophagy modulation in a ULK1-dependent manner

Man

Tan

Sun

et al. 2017

Blood

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Key Points• Loss of Caspase-3 delays leukemogenesis in a mouse model for t(8;21) AML.• Loss of Caspase-3 triggers upregulation of ULK1 and induction of autophagy in leukemia-initiating cells.AML1-ETO (AE), a fusion oncoprotein generated by t(8;21), can trigger acute myeloid leukemia (AML) in collaboration with mutations including c-Kit, ASXL1/2, FLT3, N-RAS, and K-RAS. Caspase-3, a key executor among its family, plays multiple roles in cellular processes, including hematopoietic development and leukemia progression. Caspase-3 was revealed to directly cleave AE in vitro, suggesting that AE may accumulate in a Caspase-3-compromised background and thereby accelerate leukemogenesis. Therefore, we developed a Caspase-3 knockout genetic mouse model of AML and found that loss of Caspase-3 actually delayed AML1-ETO9a (AE9a)-driven leukemogenesis, indicating that Caspase-3 may play distinct roles in the initiation and/or progression of AML. We report here that loss of Caspase-3 triggers a conserved, adaptive mechanism, namely autophagy (or macroautophagy), which acts to limit AE9a-driven leukemia. Furthermore, we identify ULK1 as a novel substrate of Caspase-3 and show that upregulation of ULK1 drives autophagy initiation in leukemia cells and that inhibition of ULK1 can rescue the phenotype induced by Caspase-3 deletion in vitro and in vivo. Collectively, these data highlight Caspase-3 as an important regulator of autophagy in AML and demonstrate that the balance and selectivity between its substrates can dictate the pace of disease. (Blood. 2017;129(20):2782-2792

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“…Increasing evidence suggests that autophagy is crucial for the generation, development and treatment of AML cells. It has been reported that deletion of FIP200 or ATG7 leads to abnormal differentiation in the hematopoietic system [19] and that chemotherapy drugs such as As 2 O 3 , cytarabine and doxorubicin induce autophagy-related cell death in AML cells [20][21][22]. Autophagy also promotes the degradation of fusion onco-proteins, including FLT3-ITD, PML-RARA and BCR-ABL, and thus provides new strategies for leukemia treatment [23][24][25].…”

Section: Clinical Characteristics Of Aml Patientsmentioning

confidence: 99%

Expression of autophagy genes in acute myeloid leukemia: associations with clinical characteristics and prognosis

Peng

Miao

Liu

et al. 2018

neo

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The relationships between autophagy-associated gene expression and clinical characteristics and prognosis in acute myeloid leukemia (AML) have not been well revealed. We examined mRNA expression of Bcl-2, p62, Beclin 1, VPS34, Rubicon, ALFY, UVRAG, ULK1, LC3 and NBR1 in 20 AML cases and 10 benign hematological cases by real-time PCR. Clinical information, treatment responses and outcomes of the AML patients were collected. Beclin 1, LC3, UVRAG, Rubicon and NBR1 were downregulated in AML patients compared with control group (P<0.05). Low ULK1 expression was associated with high white blood cell counts (P<0.05). Autophagy-associated gene expression was not correlated with chemotherapy response. Finally, we analyzed overall survival and found no obvious association with gene expression. However, in unfavorable outcome patients, low Beclin 1 and p62 expression showed worse overall survival than high-expression. Autophagy genes are associated with outcome in AML patients and may be biomarkers or targets in the future.

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Idarubicin induces mTOR-dependent cytotoxic autophagy in leukemic cells

Cited by 30 publications

References 45 publications

Nitric Oxide Interacts with Caveolin-1 to Facilitate Autophagy-Lysosome-Mediated Claudin-5 Degradation in Oxygen-Glucose Deprivation-Treated Endothelial Cells

Nitric Oxide Interacts with Caveolin-1 to Facilitate Autophagy-Lysosome-Mediated Claudin-5 Degradation in Oxygen-Glucose Deprivation-Treated Endothelial Cells

Caspase-3 controls AML1-ETO–driven leukemogenesis via autophagy modulation in a ULK1-dependent manner

Expression of autophagy genes in acute myeloid leukemia: associations with clinical characteristics and prognosis

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