As
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            targets RING-type E3 ligase c-CBL to induce degradation of BCR-ABL in chronic myelogenous leukemia

Mao, Jianhua; Sun, Xiaoyan; Liu, Jianxiang; Zhang, Qunye; Liu, Ping; Huang, Qiu-Hua; Li, Keqin Kathy; Chen, Quan; Chen, Zhu; Chen, Sai‐Juan

doi:10.1073/pnas.1016311108

Cited by 81 publications

(58 citation statements)

References 45 publications

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“…Other diseases driven by fusion oncogenes might be highly susceptible to therapies aimed at degrading the fusion protein. For example, in BCR/ABLdriven leukemia, the effect of the kinase inhibitor imatinib may be enhanced by the concomitant induction of the fusion protein degradation following arsenic treatment, via a recently discovered mechanism (73,74).…”

Section: Section Reviewmentioning

confidence: 99%

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

et al. 2011

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Many targeted therapies against cancer are aimed at inhibiting the enzymatic activity of kinases. Thus far, this approach has undoubtedly yielded significant clinical improvements, but has only rarely achieved cures. Other drugs, which selectively elicit proteasome-dependent degradation of oncoproteins, induce the loss of cancer cell self-renewal and promote cell differentiation and/or apoptosis. In acute promyelocytic leukemia, the cooperative degradation of PML/RARA by arsenic and retinoic acid cures most patients. In this condition and others, drug-induced proteolysis of oncoproteins is feasible and underlies improved clinical outcome. Several transcription factors, nuclear receptors, or fusion proteins driving cancer growth could be candidates for proteolysis-based drug-discovery programs. Summary: Some cancer therapies may degrade oncoproteins. Loss of the driver oncoprotein is associated with loss of cancer cell self-renewal. Leukemia- or sarcoma-associated fusion proteins are the best candidates for small-molecule screens aimed at initiating oncoprotein degradation. Cancer Discovery; 1(2). 117–27. ©2011 AACR.

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Section: Section Reviewmentioning

confidence: 99%

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

et al. 2011

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“…22 However, the key downstream cellular events by which such arsenic-dependent induction of autophagy elicits antileukemic responses and its potential involvement in the generation of inhibitory responses in other types of leukemias have been unknown. As AS 2 O 3 is known to induce BCR-ABL degradation, 20,23 we examined the role of autophagy in the process and in the generation of antileukemic responses in BCR-ABL expressing cells. Our studies provide evidence for a novel mechanism, involving autophagic degradation of the transforming BCR-ABL oncoprotein.…”

Section: Introductionmentioning

confidence: 99%

Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide

Goussetis

Gounaris

et al. 2012

Blood

115

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We provide evidence that arsenic trioxide (As 2 O 3 ) targets the BCR-ABL oncoprotein via a novel mechanism involving p62/ SQSTM1-mediated localization of the oncoprotein to the autolysosomes and subsequent degradation mediated by the protease cathepsin B. Our studies demonstrate that inhibitors of autophagy or ca- IntroductionElements of the autophagic machinery have attracted recently considerable attention as a potential target for the development of novel approaches for the treatment of malignancies. 1,2 Similar to apoptosis, autophagy is a programmed cell death mechanism, but it is distinguished by a self-catabolic process involving lysosomal proteolytic degradation of cellular components. 3 This is initiated by the formation of a double-membrane enclosed structure, known as the autophagosome. 4 On fusion with a lysosome, a cellular organelle characterized by low pH and hydrolytic enzymes, 5,6 such structure eventually develops into the autophagolysosome where degradation of organelles occurs.Under different circumstances, autophagy can either inhibit or promote malignant cell survival, but its precise role in tumorigenesis remains to be established. 7,8 The role of inducible autophagy in BCR-ABL expressing leukemia cells is poorly understood. For example, there is previous evidence suggesting that autophagy may play regulatory roles in BCR-ABL leukemogenesis, 9 whereas other studies have shown that pharmacologic inhibition of autophagy enhances the effects of imatinib mesylate and other targeted therapies in CML. [10][11][12] There are also opposing lines of evidence, pointing toward tumor inhibitory effects of autophagy, 13,14 although a recent study demonstrated that BCR-ABL exerts suppressive effects on autophagy via engagement of the PI3K/FoxO4/ATF5/ mTOR pathway. 15 Arsenic trioxide (AS 2 O 3 ) exhibits potent antileukemic effects in vitro and in vivo and has major clinical activity in the treatment of patients with acute promyelocytic leukemia (APL). [16][17][18] This agent was previously shown to target and eliminate leukemia initiating stem cells (LICs) in mouse models in vivo via PML targeting. 19 Notably, there is evidence that AS 2 O 3 degrades BCR-ABL, 20 raising the possibility that this agent may provide an approach to target CML LICs. However, a major limiting factor for the incorporation of arsenic in non-APL malignancies has been the requirement of high concentrations for induction of cell death in non-APL cells and the incomplete understanding of the mechanisms by which it promotes antileukemic responses.A major mechanism contributing to the antineoplastic effects of arsenic is induction of apoptosis, 16-18 with upstream JNK activation being a prominent regulatory mechanism. 21 In a recent study, we provided evidence that arsenic trioxide induces autophagy in AML leukemic progenitors and demonstrated that such autophagy is essential for generation of the inhibitory effects of arsenic on primitive leukemic precursors. 22 However, the key downstream cellular events by which such arsenic-de...

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“…However, ATO also has been found to be effective against many other hematologic malignancies and solid tumors. For example, together with imatinib it is a promising treatment for chronic myelocytic leukemia (3), and it has been used alone with some success to treat multiple myeloma (4), myelodysplasia syndrome (5), and non-Hodgkin lymphoma (6). ATO also is under clinical investigation as a possible medication for lung cancer, hepatocellular carcinoma, melanoma, renal cell carcinoma, and colorectal cancer (https://www.clinicaltrials.gov/).…”

mentioning

confidence: 99%

Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic

Zhang

Yang

Ling

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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135

101

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Arsenic is highly effective for treating acute promyelocytic leukemia (APL) and has shown significant promise against many other tumors. However, although its mechanistic effects in APL are established, its broader anticancer mode of action is not understood. In this study, using a human proteome microarray, we identified 360 proteins that specifically bind arsenic. Among the most highly enriched proteins in this set are those in the glycolysis pathway, including the rate-limiting enzyme in glycolysis, hexokinase-1. Detailed biochemical and metabolomics analyses of the highly homologous hexokinase-2 (HK2), which is overexpressed in many cancers, revealed significant inhibition by arsenic. Furthermore, overexpression of HK2 rescued cells from arsenic-induced apoptosis. Our results thus strongly implicate glycolysis, and HK2 in particular, as a key target of arsenic. Moreover, the arsenic-binding proteins identified in this work are expected to serve as a valuable resource for the development of synergistic antitumor therapeutic strategies.arsenic trioxide | human proteome microarray | glycolysis | hexokinase-2IA rsenic and its derivatives have been applied as therapy for a variety of diseases for more than 2,200 y (1). To date, the disease most successfully treated with these types of compounds is acute promyelocytic leukemia (APL). Administration of arsenic trioxide (ATO) combined with all-trans retinoic acid has demonstrated a remarkable 5-y overall survival rate of 85-90% as a consequence of the dramatic down-regulation of the key protein driving APL tumorigenicity, promyelocytic leukemia-retinoic acid receptor α (PML-RARα) (2). However, ATO also has been found to be effective against many other hematologic malignancies and solid tumors. For example, together with imatinib it is a promising treatment for chronic myelocytic leukemia (3), and it has been used alone with some success to treat multiple myeloma (4), myelodysplasia syndrome (5), and non-Hodgkin lymphoma (6). ATO also is under clinical investigation as a possible medication for lung cancer, hepatocellular carcinoma, melanoma, renal cell carcinoma, and colorectal cancer (https://www.clinicaltrials.gov/). At the cellular level, ATO has been shown to inhibit significantly the growth of almost all the cell lines (59 of 60) in the US National Cancer Institute anticancer drug screen that spans nine different tumor types (7). Thus ATO is one of the most promising broadly effective medications against cancer.Although its mode of action in APL is well established, the underlying mechanisms by which ATO acts in other types of cancers remain poorly understood. A variety of systematic studies, including studies that provided transcriptomic, chemogenomic, or proteomic characterizations (8, 9), have been performed to gain a better understanding of this broader anticancer activity of ATO. However, these studies examined only the cellular consequences of treatment with ATO without identifying the primary proteins directly bound and modulated by ATO. Knowledge of ATO...

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As ₄ S ₄ targets RING-type E3 ligase c-CBL to induce degradation of BCR-ABL in chronic myelogenous leukemia

Cited by 81 publications

References 45 publications

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide

Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic

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As 4 S 4 targets RING-type E3 ligase c-CBL to induce degradation of BCR-ABL in chronic myelogenous leukemia

Cited by 81 publications

References 45 publications

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide

Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic

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As ₄ S ₄ targets RING-type E3 ligase c-CBL to induce degradation of BCR-ABL in chronic myelogenous leukemia