Activation of the Mitogen- and Stress-activated Kinase 1 by Arsenic Trioxide

Kannan-Thulasiraman, Padma; Katsoulidis, Efstratios; Tallman, Martin S.; Arthur, J. Simon C.; Platanias, Leonidas C.

doi:10.1074/jbc.m603111200

Cited by 57 publications

(63 citation statements)

References 59 publications

(66 reference statements)

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“…An important role for mitogen-and stress-activated kinase 1 downstream of p38 in the regulation of ATO responses in leukemic cells was also proposed. 45 However, ATO-induced apoptosis in HepG 2 cells was shown to be independent of MAP kinase signaling pathways. 46 Consistent to Shim's report, 26 here we showed that ATO at 1 mM slightly activated p38 but not JNK, while bortezomib activated both JNK and p38.…”

Section: Discussionmentioning

confidence: 99%

Arsenic trioxide and proteasome inhibitor bortezomib synergistically induce apoptosis in leukemic cells: the role of protein kinase Cδ

et al. 2007

Leukemia

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Arsenic trioxide (ATO) and proteasome inhibitor bortezomib have been successfully applied to treat acute promyelocytic leukemia (APL) and multiple myeloma (MM), respectively. Their synergistic effects with other anticancer drugs have been widely studied. Here, we investigated the potential synergy of bortezomib and ATO on Bcr-Abl þ leukemic K562 cells. The results showed that cotreatment of bortezomib at 32 nM, a half concentration for growth arrest, and ATO at 1 lM, a dose with no significant cytotoxic effect, synergistically induced apoptosis in the cell line, followed by enhanced mitochondrial dysfunction, release of cytochrome c and apoptosis-inducing factor, caspase-3 cleavage and degradation of poly-adenosine diphosphate-ribose polymerase together with the decreased Bcr-Abl protein. These two drugs synergistically induced proteolytic activation of protein kinase Cd (PKCd) with enhanced activation of two mitogen-activated protein kinases phospho-c-Jun NH 2 -terminal kinase and p38. The specific PKCd inhibitor rottlerin markedly decreased bortezomib plus ATO-induced apoptosis, suggesting that PKCd plays an important role in bortezomib plus ATO-induced apoptosis. Moreover, apoptosis synergy of bortezomib and ATO could also be seen in some kinds of acute leukemic cell lines and primary cells. Totally, our results indicate that combined regimen of bortezomib and ATO might be a potential therapeutic remedy for the treatment of leukemia.

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Section: Discussionmentioning

confidence: 99%

Arsenic trioxide and proteasome inhibitor bortezomib synergistically induce apoptosis in leukemic cells: the role of protein kinase Cδ

et al. 2007

Leukemia

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“…One cascade involves activation of p70 S6K, which regulates phosphorylation of the S6 ribosomal protein and the initiation factor 4B (60 -66). The other mTOR-regulated cascade involves hierarchical phosphorylation of the translational repressor 4E-BP1 on Thr-37/46, Thr-70, and Ser-65, events that ultimately lead to its deactivation and dissociation from the eukaryotic initiation factor 4E, to allow cap-dependent translation (51)(52)(53)(54)(55)(56)(57)67). Activation of mTOR and its effectors is induced by various cytokines, hormones, and receptor tyrosine kinases, and such activation is important for the generation of mitogenic and cell proliferative responses (60 -66).…”

Section: Discussionmentioning

confidence: 99%

Suppression of Programmed Cell Death 4 (PDCD4) Protein Expression by BCR-ABL-regulated Engagement of the mTOR/p70 S6 Kinase Pathway

Carayol

Katsoulidis

Sassano

et al. 2008

Journal of Biological Chemistry

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There is accumulating evidence that mammalian target of rapamycin (mTOR)-activated pathways play important roles in cell growth and survival of BCR-ABL-transformed cells. We have previously shown that the mTOR/p70 S6 kinase (p70 S6K) pathway is constitutively activated in BCR-ABL transformed cells and that inhibition of BCR-ABL kinase activity by imatinib mesylate abrogates such activation. We now provide evidence for the existence of a novel regulatory mechanism by which BCR-ABL promotes cell proliferation, involving p70 S6K-mediated suppression of expression of programmed cell death 4 (PDCD4), a tumor suppressor protein that acts as an inhibitor of cap-dependent translation by blocking the translation initiation factor eIF4A. Our data also establish that second generation BCR-ABL kinase inhibitors block activation of p70 S6K and downstream engagement of the S6 ribosomal protein in BCR-ABL transformed cells. Moreover, PDCD4 protein expression is up-regulated by inhibition of the BCR-ABL kinase in K562 cells and BaF3/BCR-ABL transfectants, suggesting a mechanism for the generation of the proapoptotic effects of such inhibitors. Knockdown of PDCD4 expression results in reversal of the suppressive effects of nilotinib and imatinib mesylate on leukemic progenitor colony formation, suggesting an important role for this protein in the generation of antileukemic responses. Altogether, our studies identify a novel mechanism by which BCR-ABL may promote leukemic cell growth, involving sequential engagement of the mTOR/p70 S6K pathway and downstream suppression of PDCD4 expression. Chronic myeloid leukemia (CML)2 is a clonal myeloproliferative disorder, whose hallmark is the presence of the BCR-ABL oncoprotein, which results from the abnormal bcr-abl fusion oncogene (1-3). bcr-abl is created by a reciprocal translocation involving chromosomes 9 and 22, and its abnormal protein product plays a key and essential role in the pathogenesis of CML (1-4). The constitutive tyrosine kinase activity of BCR-ABL mediates phosphorylation of multiple downstream substrates and engagement of various mitogenic pathways that promote cell growth and survival (1-7). The introduction of imatinib mesylate in the management of chronic myelogenous leukemia has had a dramatic impact on the natural history of the disease (reviewed in Refs. 8 -11). This agent induces long lasting hematologic and cytogenetic responses in patients with early and late phase CML (8, 12, 13, 14, 16 -18) by its ability to block activation the BCR-ABL kinase and generation of mitogenic responses (8 -11).Although the introduction of imatinib mesylate was a major breakthrough in the management of CML, there has been emerging evidence for resistance to its antileukemic properties in vitro and in vivo (19 -22). Such resistance involves a variety of cellular mechanisms, including mutations of the bcr-abl gene, amplification of the bcr-abl gene locus, and activation of downstream signaling elements, such as Src-kinase-dependent pathways (19,(23)(24)(25)(26)(27)(28). Research ...

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“…22,[24][25][26] Immunoblotting using an enhanced chemiluminescence (ECL) methodology was performed as in our previous studies. [24][25][26][27] In the experiments in which the pharmacologic inhibitors pepstatin A and E-64d were used, the cells were pretreated for 60 minutes with the indicated concentrations of the inhibitors before the addition of AS 2 O 3 to the cultures. siRNA-mediated knockdown of Beclin 1 or Atg7 in human leukemic cells was performed using Nucleofector kits from Amaxa Biosystems.…”

Section: Cell Lysis and Immunoblottingmentioning

confidence: 99%

“…The effects of AS 2 O 3 on leukemic progenitor colony formation were assessed by clonogenic assays in methylcellulose, as previously described. 22,24,25,27 Acridine orange staining and flow cytometric analysis Formation of acidic vesicular organelles (AVOs), a morphologic characteristic of autophagy was quantitated by acridine orange staining. 28 Acridine orange (0.5 mg/mL; Invitrogen) was added 15 minutes before collection and after washing with phosphate buffered saline, cells were analyzed by flow cytometry.…”

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confidence: 99%

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

Goussetis

Gounaris

et al. 2012

Blood

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117

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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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Activation of the Mitogen- and Stress-activated Kinase 1 by Arsenic Trioxide

Cited by 57 publications

References 59 publications

Arsenic trioxide and proteasome inhibitor bortezomib synergistically induce apoptosis in leukemic cells: the role of protein kinase Cδ

Arsenic trioxide and proteasome inhibitor bortezomib synergistically induce apoptosis in leukemic cells: the role of protein kinase Cδ

Suppression of Programmed Cell Death 4 (PDCD4) Protein Expression by BCR-ABL-regulated Engagement of the mTOR/p70 S6 Kinase Pathway

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

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