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NEOPLASIA
From the Shanghai Institute of Hematology and Key
Laboratory for Human Genome Research, Rui Jin Hospital, Shanghai Second
Medical University, Shanghai, China; INSERM U496, Centre G. Hayem,
Hopital Saint Louis, Paris, France; and Division of Neoplastic
Diseases, Department of Medicine, The Mount Sinai Medical Center, New
York, NY.
Acute promyelocytic leukemia (APL) is characterized by the specific
chromosome translocation t(15;17) with promyelocytic leukemia-retinoic acid receptor- Acute promyelocytic leukemia (APL), characterized
by differentiation arrest of granulopoiesis at the promyelocytic stage, is the first human malignancy that can be efficiently treated with a
cell differentiation inducer, all-trans retinoic acid
(ATRA).1 Despite the great success of ATRA and
chemotherapy in both remission induction and maintenance therapy in
APL, a fair percentage (30%-40%) of patients still have a relapse
after initial remission and develop resistance to ATRA
treatment.2 Recently, arsenic trioxide
(As2O3), an ancient traditional Chinese
medicine, has proven to be an effective drug in the treatment of
patients with APL, not only in primary cases, but also in patients with
relapses or refractory disease after ATRA or chemotherapy or
both.3,4
It is well known that APL blasts harbor a specific translocation
t(15;17),5 fusing promyelocytic leukocyte (PML)
and retinoic acid receptor- Cyclic adenosine monophosphate (cAMP), one of the most common second
messengers, plays an important role in the response to hormonal signals
for cell proliferation, differentiation, and apoptosis, including that
in hemopoietic development.21 It was shown that cAMP was
able to induce monocytic differentiation of M1 mouse myeloid leukemia
cells22 and of HL60 cells.23 cAMP could also
potentiate granulocytic differentiation of retinoid- or
rexinoid-induced maturation of human APL cell.24-26 In the
present work, in an attempt to investigate the possible interaction
between As2O3 and several differentiation
inducers, we found that the 8-CPT (4-chlorophenylthio)-cAMP, a cAMP
analogue, synergizes with arsenic and significantly induces the
differentiation of APL cell lines NB4 and NB4-R1, which are
retinoid-induced maturation sensitive and resistant,
respectively.24,27 This synergy was also observed in fresh
APL cells. We provide here mechanistic evidence for synergic effects of
As2O3 and cAMP on APL cell maturation,
involving As2O3-induced degradation
of oncoprotein PML-RAR Cell culture and reagents
Characterization of cell differentiation
Analysis of cell cycle Briefly, cells were collected, washed, and fixed overnight in 70% cold ethanol. After washing with PBS, cells were treated by Tris-HCl buffer (pH 7.4) supplemented with 1% RNase. Cell cycle distribution was then analyzed by staining the cells with 50 µg/mL propidium iodine (PI; Sigma) and evaluated in a flow cytometer. All data were collected, stored, and analyzed by Multicycle software (Coulter, Miami, FL).Confocal immunofluorescence staining For immunofluorescence analysis, the cells were smeared onto histologic slides by using cytospin centrifugation (Shandon, Astmoor, Runcorn, Cheshire, United Kingdom). After drying, the cells were fixed in acetone at 4°C for 10 minutes and allowed to air dry for 20 minutes. The slides were preincubated for 15 minutes with PBS. PML-RAR and PML were detected with the monoclonal antiserum directed
against PML (Santa Cruz Biotechnology, Santa Cruz, CA). Fluorescein
isothiocyanate (FITC)-coupled antimouse antibody (Biosys,
Compiègne, France) was used as a second antibody. All incubations
were carried out at room temperature and followed by 3 washes in PBS;
slides were finally mounted with 5 µL fluorescent mounting medium
(Dako, Kyoto, Japan). Preparations were examined by confocal
laser scanning microscopy (MRC-600 Confocal Imaging System; Bio-Rad
Microscience, Hertfordshire, United Kingdom), mounted on an Optiphot II
Nikon microscope. Images were collected using an oil immersion lens
(× 60, NA I.4 plan Apochromat) and using excitation wavelength of 488 nm for FITC.
Western blotting analysis Whole cell protein extracts were prepared from 2 × 106 cells. Briefly, cultured cells were washed in PBS, then the pellets were immediately lysed by 100 µL of a boiling Laemmli solution containing -mercaptoethanol and disrupted with a
pestle. Samples were then boiled for 5 minutes and insoluble material
was removed by centrifugation at 13 000 rpm for 5 minutes. The quality
and the quantity of all samples were detected with sodium dodecyl sulfate (SDS)-polyacrylamide gels. The protein loading volume was
adjusted according to Coomassie blue staining. For Western analysis, 10 µg protein extracts were loaded on SDS-polyacrylamide gels, subjected
to electrophoresis, and blotted onto polyvinylidene difluoride
membranes (Amersham, Buckinghamshire, United Kingdom). To ensure that
the protein loading was as equal as possible, we generally performed 2 gels in parallel, one for transfer, another for staining with Coomassie
blue as a loading control. After transfer, membranes were blocked with
5% nonfat milk in PBS pH 7.6, 0.1% Tween-20 (PBS-T), then incubated
with a specific antiserum raised against the indicated protein in
PBS-T/3% milk for 18 hours at 4°C. Subsequently, membranes were
incubated with horseradish peroxidase (HRP)-conjugated antirabbit or
antimouse secondary antibody (Jackson Laboratories, Bar Harbor,
ME) for 30 minutes at 25°C. Each step was followed by three
10-minute washes in PBS-T. Detection was performed by using an enhanced
chemoluminescence kit (Amersham) according to the manufacturer's
instruction. All antibodies used in the present work (CDK4, cyclin D1,
E2F, p21, p27, p53) were purchased from Santa Cruz Biotechnology.
Cell transient transfection The PML-RAR expression plasmid was subcloned in pSG5 vector
as described.28 RARE-TK-luciferase reporter
plasmid contains the DR5-RARE retinoic acid response element of the
RAR upstream of thymidine kinase promoter.29 For
luciferase assay, COS-7 cells were cotransfected with 1.0 µg
PML-RAR expression plasmid and 0.1 µg RARE-TK-luciferase reporter
plasmid by using LipofectAmine reagent (Gibco BRL) according to the
manufacturer's procedure. The total amount of plasmid was adjusted to
1.1 µg using empty vector to maintain constant in all transfection
assays. Twenty-four hours after transfection, cells were respectively
treated without or with ATRA (10 nM), As2O3
(0.25 µM), or 8-CPT-cAMP (200 µM) alone or their combination for 24 hours followed by transcriptional activity assay using the luciferase
assay system (Promega, Madison, WI).
Synergism of As2O3 and several differentiation inducers Previous work showed that As2O3 at low concentration (0.1-0.25 µM) could induce a certain degree of maturation of NB4 cells. However, this differentiation is far from terminal because most cells could not mature beyond the myelocyte-metamyelocyte stage and the NBT reduction test remained negative.15 Moreover, this partial differentiation could be observed only after long (> 10 days) exposure of the cells to the drug. As shown in the Figure 1A of this work, assessed by morphologic criteria, no obvious maturation was observed in NB4 cells after treatment with arsenic alone for 4 days, except an increased number of cytoplasmic granules and vacuoles (Figure 1A). The expression of CD11b was only slightly increased (Figure 1C). Further mechanism studies showed that 0.25 µM arsenic exerted no direct effect on modulating the interaction between SMRT and the wild-type RAR/retinoid X receptor (RXR) or PML-RAR (data
not shown), although it caused increased acetylation of histones H3 and
H4 in favor of opening chromatin structure.30 It is thus
unlikely that the low-dose effect of As2O3 on
APL cells is mediated directly through RAR pathway, although the
integrity of the latter seems to be important for granulocytic
differentiation at promyelocyte stage.16 To test possible
synergistic effects between As2O3 and other
differentiation pathways, we added to the culture system different
concentrations of other inducers such as ATRA, TSA, and cAMP.
Consistent with a recent report,20 the
As2O3-induced CD11b elevation in NB4 cells
could be slightly enhanced by a physiologic
concentration (10 9 M) of ATRA and low-dose
(10 ng/mL) TSA (Z.C. et al, in preparation). However, the 2 above combinations showed a limited effect in triggering morphologic
maturation of NB4 cells and they could not significantly induce
differentiation in ATRA-induced maturation-resistant NB4 sublines such
as NB4-R1 and MR2. To our surprise, arsenic could induce an almost
terminal maturation of NB4 cells in the presence of 8-CPT-cAMP, which
on its own exhibit little differentiating effect.
Synergism of As2O3 and cAMP in inducing differentiation of NB4 and NB4-R1 cells During a 4-day dual treatment of NB4 cells with 0.25 µM As2O3 and 200 µM 8-CPT-cAMP, an increasing proportion of cells presented lobed or multiple nuclei, a reduced nucleus-cytoplasm ratio, more neutrophilic granules and vacuoles, as well as a smaller cell size and less basophilic cytoplasm (Figure 1A). Similar morphologic changes also were observed in NB4-R1 cells (Figure 1B), which have no maturation in the presence of ATRA. This situation is reminiscent of the previous report that addition of cAMP-elevating agents could trigger retinoid-primed NB4-R1 cells to undergo terminal differentiation.24,31 Our morphologic data on the cooperation between arsenic and cAMP were further supported by the results of NBT test and CD11b expression detection (Figure 1C-F). A gradual increasing of CD11b expression and of NBT+ cells was observed in both NB4 and NB4-R1 cells during the treatment by 0.25 µM As2O3 and 200 µM 8-CPT-cAMP in combination, whereas there was no prominent change in the presence of each of the inducers alone. Notably, cell maturation seemed to proceed faster in NB4-R1 cells than in NB4 cells. In line with these observations, similar synergic effects of As2O3 and cAMP were also seen in fresh cells from 2 de novo APL patients (Figure 2A-C).
Because protein kinase A (PKA) represents a major regulator in cAMP signal transduction pathway, H89, a specific PKA inhibitor, was further used to examine the possible role of PKA pathway in the differentiation of NB4 and NB4-R1 cells induced by As2O3 or cAMP or both. Indeed, H89 was able to decrease the As2O3-triggered CD11b expression of NB4 cells in a weak but significant way (Figure 1G). Moreover, this PKA inhibitor could dramatically inhibit the differentiation of NB4 and NB4-R1 cells induced by the combination of As2O3 and cAMP judging from CD11b expression (Figure 1G), NBT reduction activity (Figure 1H), and morphologic change (data not shown). These observations suggested that the synergism effect of As2O3 and cAMP in inducing differentiation of APL cells might reside at the PKA level. Inhibition of cell growth induced by As2O3 or cAMP in NB4 and NB4-R1 cells Next, the effects of As2O3, 8-CPT-cAMP or their combination on the growth of NB4 and NB4-R1 cells were examined. Only a slight decrease in cell growth was observed in NB4 and NB4-R1 cells treated with arsenic alone (Figures 3A and 4A). In contrast, the growth of both cells could be dramatically inhibited by 8-CPT-cAMP alone or As2O3 combined with cAMP, particularly in NB4-R1 cells. The proliferation of NB4-R1 cells was almost completely inhibited within 2 days (Figure 4A). In agreement with this, analysis of the cell cycle distribution showed that NB4 and NB4-R1 cells significantly accumulated at the G0/G1 phase under 8-CPT-cAMP treatment alone or when As2O3 and 8-CPT-cAMP treatments were combined, but not in the presence of As2O3 alone (Figures 3B and 4B). These data suggest that the cAMP pathway should play an important role in the inhibition of cell cycle.
To further understand the G1 phase arrest of NB4 and NB4-R1 cells in the presence of 8-CPT-cAMP alone or in combination with As2O3, we examined the expression level of several G1/S transition-related proteins. Although some positive regulatory proteins for the cell cycle, such as CDK4 and cyclin D1, seemed unchangeable during the treatment, E2F, a protein necessary for the progression of the cell into S phase, was greatly down-regulated in both cells treated by 8-CPT-cAMP. It has been well known that p21 and p27, 2 important cyclin kinase inhibitors, negatively regulate the progression from G1 into S phase.32-34 Here we showed a dramatic increase of p21 during 8-CPT-cAMP treatment of NB4 and NB4-R1 cells, whereas p27 showed little change (Figures 3C and 4C). Furthermore, we demonstrated that this up-regulation of p21 was p53 independent despite the existence of transcriptional targets of p53 in the promoter of the p21 gene.35-37 Noteworthy, all the above proteins showed no variations when the cells were treated with arsenic alone. These observations supported the notion that cAMP may play a major role in inducing G1 arrest and cell cycle exit of NB4 and NB4-R1 cells. As2O3-associated PML-RAR onto nuclear bodies (NBs) and induces their degradation.14,15,19 In the present work, confocal
microscopy was used to analyze intracellular distribution of PML and
PML-RAR in NB4 and NB4-R1 cells in the context of arsenic and cAMP
synergism. As shown in Figure 5A, the
abnormally organized fine and numerous labeled micro-PML-NBs in these 2 cell lines were modified by 0.25 µM As2O3,
with the number of NBs gradually decreased, and the size of these
structures increased. Moreover, this process was accelerated by the
addition of 8-CPT-cAMP which, on its own, failed to cause NB
reorganization. In accordance with this, Western blot analysis with
anti-RAR antibodies showed that in the presence of 8-CPT-cAMP,
As2O3 caused a near total degradation of
PML-RAR (Figure 5B) as well as the wild-type PMLs (data not shown),
whereas 8-CPT-cAMP alone did not cleave the chimeric protein (Figure
5B). These observations suggested that the PML-RAR differentiation block in NB4 and NB4-R1 cells can be, to some degrees, partially released by As2O3-induced degradation,
diminishing the dominant effect of PML-RAR. This conclusion was
further supported by data from in vitro transient transactivation on a
DR5 reporter (Figure 5C). We showed that PML-RAR inhibited the
endogenous transcriptional activity of RAR and that this
dominant-negative effect was abrogated by As2O3
alone or combined with 8-CPT-cAMP, but not by 8-CPT-cAMP alone.
Currently, ATRA and arsenic are specific drugs available
for the treatment of patients with APL. It has been known that ATRA, under both in vitro and in vivo conditions, induces terminal
differentiation (followed by natural apoptosis) of malignant cells. The
underlying molecular mechanisms include the modulation of PML-RAR However, a number of issues should be clarified and further addressed. First, the differentiation of APL cells induced by arsenic is by no means a complete one, in that most cells are blocked at the metamyelocyte stage in both in vivo and in vitro settings. Second, the mechanisms underlying this incomplete or partial differentiation are still obscure. Third, the differentiation phenomenon observed in vitro may not really reflect that in vivo, because many naturally existing differentiation regulators, including the physiologic concentrations of retinoids, could be cooperating with the therapeutic effect of arsenic in patients. To this end, it is noteworthy that in a mice APL model, the induced leukemia could be cured by the association of ATRA with arsenic through enhanced differentiation and apoptosis, whereas the use of one of the drugs on its own only prolonged survival but did not produce complete cure.17 In this study, we found that not only ATRA and the histone deacetylase inhibitor TSA, but particularly cAMP, synergized with arsenic and triggered maturation of APL cells. It has been well known that, as a ubiquitous second messenger, cAMP plays a pivotal role in the proliferation and differentiation of human myeloid, lymphoid, and erythroid progenitor cells. Strikingly, cAMP can substantially enhance the differentiating effect of As2O3 not only on ATRA-sensitive NB4 parental cells, but also on NB4-R1 cells characterized by resistance to the ATRA-induced maturation, as shown by morphologic criteria (Figure 1A,B), expression of CD11b integrin (Figure 1C,D), and the NBT test (Figure 1E,F). Moreover, this ability of cAMP was also observed in fresh APL cells (Figure 2A-C). Thus, investigation of the mechanisms underlying the synergy between cAMP and As2O3 may shed new light on the differentiation therapy. It has long been recognized that signals that stimulate cell cycle progression usually produce a block in differentiation, whereas interventions that produce a cell cycle arrest sensitize cells to the induction of differentiation.39,40 In fact, many pharmacologic differentiating agents, including phorbol esters, phenylbutyrate, and retinoids, share a common biologic activity to inhibit cell cycling.41-43 Our data showed that cAMP could cause a marked inhibition of NB4 and NB4-R1 cell proliferation by preventing these cells from entering into S phase (Figures 3B and 4B). Furthermore, we found that in the presence of cAMP, the mitotic inhibitor p21 was dramatically up-regulated in both NB4 and NB4-R1 cells, whereas the cellular transcription factor E2F greatly down-regulated (Figures 3C and 4C). p21 has been considered to best inhibit cyclin/cdk (cyclin-dependent kinase) complexes involving cdk2 and cdk4 at the G1, G1/S, and S phases and transitions in the cell cycle,32,33 and E2F has been shown to be able to regulate a number of genes that encode proteins with putative functions in the G1 to S phases of the cell cycle.44 These results strongly indicated that cAMP could exert an antiproliferative effect on myeloid cells. In contrast, no expression modulation of these cell cycle regulatory proteins was observed in the presence of arsenic alone. Nevertheless, the fact that cAMP alone was unable to induce differentiation in both NB4 and NB4-R1 cells suggested that full induction of terminal differentiation after induction of cell cycle arrest required additional lineage-specific signals. In the case of APL, the fusion protein PML-RAR Based on the above data, we may propose the following scenario.
Although neither arsenic nor cAMP is sufficient alone in promoting terminal differentiation, these 2 signals cooperated to induce the
maturation of APL cells. The cooperation might result from the
concomitant degradation of fusion protein PML-RAR In summary, our study demonstrated the existence of synergism between arsenic and cAMP that triggers maturation pathway for APL cells. It is suggested that differentiation of arsenic-induced APL cells in vivo may probably result from cooperative effects of arsenic with other factors present in the cellular microenvironment of patients with APL. In addition, the demonstration that the combined treatment of arsenic with cAMP induces the maturation not only in NB4 but also in NB4-R1 cells might to some extent account for the effective improvement in the arsenic treatment of patients with relapsed APL who are resistant to ATRA and conventional chemotherapy. Finally, consideration of the facts that chronic toxicity and carcinogenicity of As2O3 has been reported and that the toxic and cumulative effect of As2O3 is dose dependent, our work may encourage the trials of new treatment protocols for the differentiation therapy of cancer.
The authors are grateful to Dr E. Ségal-Bendirdjian for help in reviewing the manuscript. The authors acknowledge Prof Zhen-yi Wang and Prof Ting-dong Zhang for their continuous support and all members of SIH for their encouragement and constructive discussion.
Submitted June 4, 2001; accepted September 25, 2001.
Supported in part by the National Key Program for Basic Research (973), the National Natural Science Foundation of China, the Shanghai Commission for Education, the Shanghai Commission for Science and Technology, the Shanghai "New Star" Research Program, L'Association Franco-Chinoise pour la Recherche Scientifique et Technique (PRA), L'Association pour la Recherche contre le Cancer (ARC), the Samuel Waxman Cancer Research Foundation, and the Clyde Wu Foundation of Shanghai Institute of Hematology (SIH).
Q.Z. and J-W.Z. contributed equally to this work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Dr Jian-Hua Tong and Zhu Chen, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Second Medical University, 197 Rui Jin Road II, Shanghai, 200025, P. R. China; e-mail: jhtong{at}yahoo.com.
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Abstract
Introduction
