Induction of autophagy by Imatinib sequesters Bcr‐Abl in autophagosomes and down‐regulates Bcr‐Abl protein

Elzinga, Baukje M.; Nyhan, Michelle J.; Crowley, Lisa C.; O’Donovan, Tracey R.; Cahill, Mary R.; McKenna, Sharon L.

doi:10.1002/ajh.23428

Cited by 51 publications

(38 citation statements)

References 33 publications

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“…It has been demonstrated that imatinib therapy-induced autophagy degrades the Bcr-Abl oncoprotein in CML cells. 47 Taken together, these results indicated that realgar NPs induced Bcr-Abl fusion protein degradation probably via autophagy pathway in CML cells, but the exact mechanism of fusion protein degradation remains to be further investigated.…”

mentioning

confidence: 81%

Caveolin-1 contributes to realgar nanoparticle therapy in human chronic myelogenous leukemia K562 cells

Shi

Liu

et al. 2016

IJN

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confidence: 81%

Caveolin-1 contributes to realgar nanoparticle therapy in human chronic myelogenous leukemia K562 cells

Shi

Liu

et al. 2016

IJN

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“…Studies have shown that the FDA-approved anti-diabetic drug metformin can induce autophagy activity (Kalender et al, 2010; Jiang et al, 2014). In addition, several autophagy-inducing compounds, such as rapamycin, trehalose or imatinib, have been tested on animal models of diabetes and have shown beneficial effects on insulin sensitivity and β cells protection (Newgard et al, 2009; Zhou et al, 2009; Gonzalez et al, 2011; Elzinga et al, 2013; Marselli et al, 2013;). However, future investigations will be necessary to analyze whether the beneficial effects of these drugs are directly through autophagy.…”

Section: Systematic Autophagy In Metabolic Diseasesmentioning

confidence: 99%

Emerging roles of autophagy in metabolism and metabolic disorders

Rocchi

2015

Front. Biol.

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The global prevalence of metabolic disorders is an immediate threat to human health. Genetic features, environmental aspects and lifestyle changes are the major risk factors determining metabolic dysfunction in the body. Autophagy is a housekeeping stress-induced lysosomal degradation pathway, which recycles macromolecules and metabolites for new protein synthesis and energy production and regulates cellular homeostasis by clearance of damaged protein or organelles. Recently, a dramatically increasing number of literatures has shown that defects of the autophagic machinery is associated with dysfunction of multiple metabolic tissues including pancreatic β cells, liver, adipose tissue and muscle, and is implicated in metabolic disorders such as obesity and insulin resistance. Here in this review, we summarize the representative works on these topics and discuss the versatile roles of autophagy in the regulation of cellular metabolism and its possible implication in metabolic diseases.

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“…4,5 However, autophagy has also been suggested to be a mediator of cell death in certain contexts, 6 and it was recently demonstrated that autophagy facilitates basal and therapy-induced degradation of promyelocytic leukemia-retinoic acid receptor a (PML-RARA) and breakpoint cluster region-abelson, 2 frequently occurring fusion oncoproteins associated with acute promyelocytic leukemia and chronic myeloid leukemia (CML), respectively. [7][8][9][10] Thus, in these instances, one would seek therapeutic options where autophagy is activated, rather than inhibited.…”

Section: Introductionmentioning

confidence: 99%

Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells

Torgersen

Engedal

Bøe

et al. 2013

Blood

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Key Points• In AML1-ETO-positive AML cells, HDAC inhibitors induce autophagy, which acts as a prosurvival signal to limit HDAC-induced cell death.• In contrast to the fusion oncoproteins PML-RARA and breakpoint cluster regionabelson, AML1-ETO is not degraded by either basal-or drug-induced autophagy.The role of autophagy during leukemia treatment is unclear. On the one hand, autophagy might be induced as a prosurvival response to therapy, thereby reducing treatment efficiency. On the other hand, autophagy may contribute to degradation of fusion oncoproteins, as recently demonstrated for promyelocytic leukemia-retinoic acid receptor a and breakpoint cluster region-abelson, thereby facilitating leukemia treatment. Here, we investigated these opposing roles of autophagy in t(8;21) acute myeloid leukemia (AML) cells, which express the most frequently occurring AML fusion oncoprotein, AML1-eight-twenty-one (ETO). We demonstrate that autophagy is induced by AML1-ETO-targeting drugs, such as the histone deacetylase inhibitors (HDACis) valproic acid (VPA) and vorinostat. Furthermore, we show that autophagy does not mediate degradation of AML1-ETO but rather has a prosurvival role in AML cells, as inhibition of autophagy significantly reduced the viability and colony-forming ability of HDACi-treated AML cells. Combined treatment with HDACis and autophagy inhibitors such as chloroquine (CQ) led to a massive accumulation of ubiquitinated proteins that correlated with increased cell death. Finally, we show that VPA induced autophagy in t(8;21) AML patient cells, and combined treatment with CQ enhanced cell death. Because VPA and CQ are well-tolerated drugs, combinatorial therapy with VPA and CQ could represent an attractive treatment option for AML1-ETO-positive leukemia. (Blood. 2013;122(14):2467-2476) IntroductionMacroautophagy, hereafter referred to as autophagy, is a catabolic pathway that is upregulated during times of nutrient limitations or stress to maintain cellular metabolism and organelle integrity. 1Autophagy involves sequestration of cytoplasmic cargo, such as long-lived proteins, damaged organelles, and protein aggregates, into double-membrane vesicles termed autophagosomes, which fuse with lysosomes, leading to degradation of the contents by acidic hydrolases. 1 There is currently a pressing need to understand in which settings autophagy should be inhibited and in which instances autophagy should be activated, to overcome drug resistance and optimize cancer treatment. Recent studies indicate that anticancer treatment may be hampered by the activation of autophagy as a prosurvival mechanism that prevents apoptosis and delays necrosis in the cancer cells. 2,3 Thus, including autophagy inhibitors in cancer therapy could potentially overcome cancer drug resistance. 4,5 However, autophagy has also been suggested to be a mediator of cell death in certain contexts, 6 and it was recently demonstrated that autophagy facilitates basal and therapy-induced degradation of promyelocytic leukemia-retinoic acid receptor a (P...

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Induction of autophagy by Imatinib sequesters Bcr‐Abl in autophagosomes and down‐regulates Bcr‐Abl protein

Cited by 51 publications

References 33 publications

Caveolin-1 contributes to realgar nanoparticle therapy in human chronic myelogenous leukemia K562 cells

Caveolin-1 contributes to realgar nanoparticle therapy in human chronic myelogenous leukemia K562 cells

Emerging roles of autophagy in metabolism and metabolic disorders

Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells

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