Activation of mammalian target of rapamycin and the p70 S6 kinase by arsenic trioxide in BCR-ABL–expressing cells

Yoon, Patrick; Giafis, Nick; Smith, Jenna; Mears, Heather; Katsoulidis, Efstratios; Sassano, Antonella; Altman, Jessica K.; Redig, Amanda J.; Tallman, Martin S.; Platanias, Leonidas C.

doi:10.1158/1535-7163.mct-06-0263

Cited by 24 publications

(19 citation statements)

References 46 publications

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“…No significant differences in p70S6K phosphorylation compared with controls were observed in nonresponding sample AML710 (supplemental Figure 1, available on the Blood website; see the Supplemental Materials link at the top of the online article). Interestingly, similar p70S6 and S6 kinase phosphorylation patterns have been demonstrated in CML cells exposed to arsenic 21 and hepatocytes exposed to phosphatase-inhibitory toxins. 22 To further implicate the p70S6K pathway in SB's cytopathic effect, we first inhibited p70SK phosphorylation with rapamycin in AML 774 (primary cells) and MOLM 14 cells, and then exposed those cells to SB.…”

Section: Resultssupporting

confidence: 62%

A prototype nonpeptidyl, hydrazone class, thrombopoietin receptor agonist, SB-559457, is toxic to primary human myeloid leukemia cells

Kalota

Gewirtz

2010

Blood

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Section: Resultssupporting

confidence: 62%

A prototype nonpeptidyl, hydrazone class, thrombopoietin receptor agonist, SB-559457, is toxic to primary human myeloid leukemia cells

Kalota

Gewirtz

2010

Blood

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“…In particular, activation of the p38 MAPK and its effectors Msk1 and Mnk1 (15,16,23,44) result in generation of antiapoptotic responses in AML cells (44 -46), as well as in multiple myeloma cells (45). Similarly, arsenic-induced engagement of the AKT/mTOR pathway appears to exhibit negative regulatory effects on the generation of the suppressive effects of As 2 O 3 on leukemic hematopoiesis (18,46). Such studies have suggested that combinations of As 2 O 3 with inhibitors of MAPK or mTOR pathways may provide a novel approach to overcome leukemic cell resistance in certain cases.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Is a Critical Mechanism for the Induction of the Antileukemic Effects of Arsenic Trioxide

Goussetis

Altman

Glaser

et al. 2010

Journal of Biological Chemistry

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117

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Arsenic trioxide (As 2 O 3 ) exhibits potent antitumor effects in vitro and in vivo, but the precise mechanisms by which it generates such responses are not well understood. We provide evidence that As 2 O 3 is a potent inducer of autophagy in leukemia cells. Such induction of autophagy by As 2 O 3 appears to require activation of the MEK/ERK pathway but not the AKT/mammalian target of rapamycin or JNK pathways. In efforts to understand the functional relevance of arsenic-induced autophagy, we found that pharmacological inhibitors of autophagy or molecular targeting of beclin 1 or Atg7 results in reversal of the suppressive effects of As 2 O 3 on leukemic cell lines and primary leukemic progenitors from acute myelogenous leukemia patients. Altogether, our data provide direct evidence that autophagic cell death is critical for the generation of the effects of As 2 O 3 on acute myelogenous leukemia cells and raise the potential of modulation of elements of the autophagic machinery as an approach to enhance the antitumor properties of As 2 O 3 and possibly other heavy metal derivatives. Arsenic trioxide (As 2 O 3 )2 is a metalloid that exhibits potent antineoplastic effects in vitro and in vivo (1-3). This arsenic derivative induces apoptosis and suppresses the growth of various types of malignant cells of diverse origin in vitro (1-3). Different mechanisms by which As 2 O 3 promotes cell death of target cells have been extensively studied and described (reviewed in Refs. 1-3). As 2 O 3 -dependent generation of reactive oxygen species leads to activation of pro-apoptotic pathways in different types of cells (1-3). In addition, there is evidence for mechanisms involving As 2 O 3 -dependent cell typespecific targeting of malignant cells with distinct molecular abnormalities (reviewed in Ref.3). For instance, there is evidence for As 2 O 3 -dependent specific targeting of cells expressing AML1/MDS1/EVI1 involving degradation of the abnormal fusion protein (4), evidence for arsenic-dependent BCR-ABL ubiquitination and proteasomal degradation (5), and eradication of leukemia-initiating cells in acute promyelocytic leukemia via As 2 O 3 -inducible PML-RAR␣ degradation (6).Despite extensive research over the years, the precise mechanisms of action of arsenic trioxide in malignant cells are not well understood. In particular, the specific cellular events that account for differential sensitivity of malignant cells to As 2 O 3 remain to be precisely defined. Notably, arsenic trioxide treatment induces responses in patients with acute promyelocytic leukemia in vivo (7,8), and it is an agent approved by the United States Food and Drug Administration for the treatment of this leukemia. The unusually high sensitivity of acute promyelocytic leukemia cells to the effects of arsenic trioxide likely reflects the requirement of lower As 2 O 3 concentrations for induction of leukemic cell differentiation seen in these cells versus apoptotic cell death (3), but other mechanisms may be involved as well.Autophagy is a cell death mechani...

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“…The effects of arsenic trioxide on the growth of leukemic progenitors were assessed by clonogenic assays in methylcellulose, as in previous studies (24,31,33,34). The cells were cultured in the presence or absence of As 2 O 3 (0.5 M) in the presence or absence of the indicated concentration of CGP57380 (10 M).…”

Section: Methodsmentioning

confidence: 99%

Regulation of Arsenic Trioxide-induced Cellular Responses by Mnk1 and Mnk2

Dolniak

Katsoulidis

Carayol

et al. 2008

Journal of Biological Chemistry

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The use of arsenic-containing compounds in the treatment of leukemias and other malignancies dates several decades back in time (1). Despite the known existence of arsenic compounds for hundreds of years, only recently has a derivative of this heavy metal, arsenic trioxide (As 2 O 3 ), found an established role in the treatment of a human disease. Extensive work has now established that As 2 O 3 exhibits potent pro-apoptotic effects against malignant cells and has important antineoplastic activities in vitro and in vivo (2-6). Importantly, As 2 O 3 has been approved for the treatment of acute promyelocytic leukemia (APL) 2 in humans, and its introduction in the therapy of this form of acute leukemia has had a major impact in medical oncology (1,(7)(8)(9)(10). Notably, APL is a form of leukemia with unusual sensitivity to the effects of arsenic trioxide. It is well established that induction of differentiation of APL cells occurs at low concentrations (0.5 M), whereas higher (Ն2 M) concentrations are required for the generation of its pro-apoptotic effects in other cell types (2-6). As 2 O 3 is also currently under investigation for the treatment of other hematological malignancies and clonal disorders, including chronic myelogenous leukemia, multiple myeloma, and myelodysplastic syndromes (2, 4, 11-13). A remaining challenge in introducing arsenic trioxide in the treatment of other malignancies is the development of means to enhance arsenic-dependent apoptosis at lower final concentrations. Thus, identification of cellular pathways that could be targeted to enhance the antineoplastic properties of As 2 O 3 are of high translational potential and interest.Previous work has suggested that the pro-apoptotic effects of As 2 O 3 on APL cells correlate with targeting and degradation of the abnormal PML-RAR␣ fusion protein (5, 14, 15), although independent mechanisms also exist (16). Among the genes regulated by the PML-RAR␣ fusion protein is the mitogen-activated protein kinase (MAPK)-interacting kinase 1 (Mnk1) (17, 18), a kinase that was recently shown to be post-translationally stabilized by PML-RAR␣ fusion protein and participate in the control of differentiation of myeloid cells (19). Mnk1 and the related Mnk2 are known to be activated downstream of MAPKs, via phosphorylation at Thr-197 and Thr-202 located in their activation loop (20 -23), and after their activation, they in turn phosphorylate the cap binding eukaryotic initiation factor 4E (eIF4E) at Ser-209 in response to mitogens and stress signals (22,23).In previous work, we had demonstrated that the p38 MAPK is activated in response to treatment of leukemic cells with As 2 O 3 (24) and shown that such activation occurs in a negative feedback regulatory manner, to control and limit arsenic-dependent apoptosis. This was established by studies demonstrating that pharmacological inhibitors of p38 promote generation of As 2 O 3 -dependent apoptosis (24), whereas pro-apoptotic * This work was supported by National Institutes of Health Grants CA121192, CA77816, a...

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Activation of mammalian target of rapamycin and the p70 S6 kinase by arsenic trioxide in BCR-ABL–expressing cells

Cited by 24 publications

References 46 publications

A prototype nonpeptidyl, hydrazone class, thrombopoietin receptor agonist, SB-559457, is toxic to primary human myeloid leukemia cells

A prototype nonpeptidyl, hydrazone class, thrombopoietin receptor agonist, SB-559457, is toxic to primary human myeloid leukemia cells

Autophagy Is a Critical Mechanism for the Induction of the Antileukemic Effects of Arsenic Trioxide

Regulation of Arsenic Trioxide-induced Cellular Responses by Mnk1 and Mnk2

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