The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase.

Cavigelli, Martin; Li, W. W.; Lin, Anning; Su, Bing; Yoshioka, Katsuji; Karin, Michael

doi:10.1002/j.1460-2075.1996.tb01017.x

Cited by 394 publications

(285 citation statements)

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“…It was reported previously that arsenite caused the activation of both JNK and p38 but did not affect ERK in HeLa cells 42 and in NIH 3T3 cells. 36 When pheochromocytoma PC12 cells were treated with arsenite, JNK was activated, but ERK activity was unchanged.…”

Section: Discussionmentioning

confidence: 66%

Apoptosis induced by arsenic trioxide in leukemia U937 cells is dependent on activation of p38, inactivation of ERK and the Ca2+-dependent production of superoxide

2001

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The mechanism of the induction of apoptosis by arsenic trioxide (As 2 O 3 ), which was demonstrated recently to be an effective inducer of apoptosis in patients with leukemia, was examined in detail in human leukemia U937 cells. Upon treatment of U937 cells with 50 M of As 2 O 3 , complete inactivation of the kinases ERK1 and ERK2 was detected within 30 min. p38 was activated within 3 hr, and the maximum activity was detected at 6 hr, when DNA fragmentation remained undetectable. Experiments with transfected cells that expressed constitutively activated MEK1 and a specific inhibitor of p38 also suggested that inactivation of ERKs and activation of p38 might be associated with the induction of apoptosis by As 2 O 3 . In contrast to the inactivation of ERKs and the activation of p38, activation of JNK by Key words: arsenic trioxide; apoptosis; leukemia cells; superoxide; tumorArsenic has long been used in traditional Chinese medicine. Arsenic trioxide (As 2 O 3 ) was recently demonstrated to be an effective inducer of apoptosis in patients with relapsed acute promyelocytic leukemia (APL) and in patients with APL in whom all-trans-retinoic acid (ATRA) and conventional chemotherapy has failed. 1-4 Studies in vitro indicate that As 2 O 3 can induce apoptosis in myeloma cell lines, in plasma cells from myeloma patients, 5 in malignant lymphocytic cell lines 6,7 as well as primary cultures of lymphocytic leukemia and lymphoma cells, 6 in myeloid and B-cell leukemia cell lines, 8 in megakaryocytic leukemia cell lines, 9 in neuroblastoma cell lines 10 and in HPV16-immortalized human cervical epithelial cells. 11 The mechanism responsible for the induction of apoptosis has not been fully characterized, but As 2 O 3 induced apoptosis in NB4 cells, cloned from a relapsed patient with APL, by inducing loss of PML/RAR␣ protein 12 and by suppressing expression of the Bcl-2 protein. 13 Apoptosis induced by As 2 O 3 and by the organic arsenical melarsoprol in myeloid leukemia cell lines, such as the HL-60, KG-1 and U937 cell lines, was found, however, to be independent of the level of expression of PML and PML-RAR␣. 14 In contrast to its apparent curative effects, As 2 O 3 is known to be a carcinogen in human organs, such as skin and lung, and it has serious side effects such as fluid retention in patients. 15 Other chronic side effects include polyneuropathy, palmar keratosis and skin hyperpigmentation. 15 It is, therefore, desirable to develop other drugs that act by a similar mechanism to that of As 2 O 3 but lack the side effect. While the mechanism of the induction of apoptosis in tumor cells by As 2 O 3 is not well understood, As 2 O 3 has been used to mimic the effects of heat shock on cells. 16 When rat fibroblastic 3Y1 cells and rat PC12 cells are treated with As 2 O 3 , stress-induced kinases such as c-Jun N-terminal kinase (JNK) and p38 are activated. 17 To clarify the mechanism of induction of apoptosis in tumor cells by As 2 O 3 , we examined the effects of As 2 O 3 on the activities of mitogen-activated protein (M...

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Section: Discussionmentioning

confidence: 66%

Apoptosis induced by arsenic trioxide in leukemia U937 cells is dependent on activation of p38, inactivation of ERK and the Ca2+-dependent production of superoxide

2001

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“…9). On the other hand, stimulation of growth factor receptors by arsenite accelerates the MAPK/JNK signaling pathways [9,60] that activates cJun, cFos and ATF2 transcription factors, which control transcription of both TRAIL and TRAIL-R1/R2 genes [26,27] (see Fig. 9).…”

Section: Discussionmentioning

confidence: 99%

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

Ivanov

Hei

2006

Experimental Cell Research

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AP-1/cJun, NF-κB and STAT3 transcription factors control expression of numerous genes, which regulate critical cell functions including proliferation, survival and apoptosis. Sodium arsenite is known to suppress both the IKK-NF-κB and JAK2-STAT3 signaling pathways and to activate the MAPK/JNK-cJun pathways, thereby committing some cancers to undergo apoptosis. Indeed, sodium arsenite is an effective drug for the treatment of acute promyelocytic leukemia with little nonspecific toxicity. Malignant melanoma is highly refractory to conventional radio-and chemotherapy. In the present study we observed strong effects of sodium arsenite treatment on upregulation of TRAILmediated apoptosis in human and mouse melanomas. Arsenite treatment upregulated surface levels of death receptors, TRAIL-R1 and TRAIL-R2, through increased translocation of these proteins from cytoplasm to the cell surface. Furthermore, activation of cJun and suppression of NF-κB by sodium arsenite resulted in upregulation of the endogenous TRAIL-and downregulation of the cFLIP gene expression (which encodes one of the main anti-apoptotic proteins in melanomas) followed by cFLIP protein degradation and, finally, by acceleration of TRAIL-induced apoptosis. Direct suppression of cFLIP expression by cFLIP RNAi also accelerated TRAIL-induced apoptosis in these melanomas, while COX-2 suppression substantially increased levels of both TRAIL-induced and arsenite-induced apoptosis. In contrast, overexpression of permanently active AKTmyr inhibited TRAIL-mediated apoptosis via down-regulation of TRAIL-R1 levels. Finally, AKT overactivation increased melanoma survival in cell culture and dramatically accelerated growth of melanoma transplant in vivo, highlighting a role of AKT suppression for effective anti-cancer treatment.

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“…There appears to be a reasonably linear relationship between the degree of oxidative stress, the formation of disul®de species and the induction of stress responsive proteins. Thioredoxin has been the best characterized cysteine-rich redoxresponsive protein implicated in the regulation of several stress responsive proteins via direct or intermediate interactions (reviewed in Schulze-Ostho et al, 1995; Sen and Packer, 1996; Flohe et al, 1997; Kuo et al, 1995Cavigelli et al, 1996Ludwig et al, 1998Kilk et al, 1996Lim et al, 1997Duhe et al, 1998Krejsa et al, 1997Kang et al, 1998Lui et al, 1998 Piette et al, 1997). The recent identi®cation of thioredoxin as an inhibitor of stress kinase ASK1 (Saitoh et al, 1998), has shed new light on the modes of redox regulatable stress response.…”

Section: Ros-induced Modi®cation Of Redox Sensitive Proteins Which Rementioning

confidence: 99%

Role of redox potential and reactive oxygen species in stress signaling

et al. 1999

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Stress-activated signaling cascades are a ected by altered redox potential. Key contributors to altered redox potential are reactive oxygen species (ROS) which are formed, in most cases, by exogenous genotoxic agents including irradiation, in¯ammatory cytokines and chemical carcinogens. ROS and altered redox potential can be considered as the primary intracellular changes which regulate protein kinases, thereby serving as an important cellular component linking external stimuli with signal transduction in stress response. The mechanisms, which underlie the ROS-mediated response, involve direct alteration of kinases and transcription factors, and indirect modulation of cysteine-rich redox-sensitive proteins exempli®ed by thioredoxin and glutathione Stransferase. This review summarizes the current understanding of the mechanisms contributing to ROS-related changes in key stress activated signaling cascades.

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The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase.

Cited by 394 publications

References 60 publications

Apoptosis induced by arsenic trioxide in leukemia U937 cells is dependent on activation of p38, inactivation of ERK and the Ca2+-dependent production of superoxide

Apoptosis induced by arsenic trioxide in leukemia U937 cells is dependent on activation of p38, inactivation of ERK and the Ca2+-dependent production of superoxide

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

Role of redox potential and reactive oxygen species in stress signaling

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