Research ArticleExperimental Studies
Open Access

Dimethyl Fumarate Suppresses the Proliferation of HTLV-1-infected T Cells by Inhibiting CBM Complex-triggered NF-GraphicB Signaling

TSUYOSHI SATO, TAKAHIRO MAETA and SHIGEKI ITO
Anticancer Research May 2023, 43 (5) 1901-1908; DOI: https://doi.org/10.21873/anticanres.16349

Abstract

Background/Aim: Adult T-cell leukemia (ATL) is a peripheral T-lymphocytic malignancy influenced by human T-cell leukemia virus type 1 (HTLV-1) infection. Aggressive ATL has a poor prognosis, therefore newer agents are desperately needed. We revealed that dimethyl fumarate (DMF) causes ATL cell death via inhibition of nuclear factor-kappa B (NF-Embedded ImageB) and signal transducer and activator of transcription 3 signaling. Here, we evaluated the specific mechanism of DMF effects on NF-Embedded ImageB signaling in MT-2 HTLV-1-infected T-cells. Materials and Methods: We examined the effects of DMF on the caspase recruitment domain family member 11 (CARD11)–BCL10 immune signaling adaptor (BCL10)–mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) (CBM) complex and upstream signaling molecules which are critical for NF-Embedded ImageB signaling in MT-2 cells by immunoblotting. We also explored its effects on cell-cycle distribution. Furthermore, we assessed whether the BCL2 apoptosis regulator (BCL2)/BCL2-like 1 (BCL-xL) inhibitor navitoclax promoted the inhibitory effect of DMF on cell proliferation and apoptosis-associated proteins by trypan blue exclusion test and immunoblotting, respectively. Results: DMF inhibited constitutive phosphorylation of CARD11 followed by suppression of inhibitory-Embedded ImageB kinase α/β phosphorylation at serine in a dose-dependent fashion in MT-2 cells. Furthermore, DMF inhibited MALT1 and BCL10 expression in the same fashion. However, DMF did not prevent the phosphorylation of protein kinase C-β, an upstream signaling molecule of CARD11. Cell-cycle analysis highlighted that DMF treatment at 75 μM resulted in the accumulation of cells at the sub-G1 and G2/M phases. Navitoclax modestly promoted DMF-induced suppression of MT-2 cells via inhibition of cellular inhibitor of apoptosis protein-2 expression and c-JUN N-terminal kinase phosphorylation. Conclusion: The suppression of MT-2 cell proliferation by DMF makes its further evaluation as an innovative agent for therapy of ATL worthwhile.

Key Words:

Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-lymphocytic malignancy influenced by human T-cell leukemia virus type-1 (HTLV-1) infection (1, 2). Currently, HTLV-1 carriers exist globally, particularly in endemic regions including Japan, the Caribbean islands, South America, and intertropical Africa (1, 3). The three modes of HTLV-1 transmission are mother to child, sexual transmission, and transmission via contaminated blood products. About 6-7% of male and 2-3% of female HTLV-1 carriers develop ATL after a latency period of 30-50 years from infection. Patients with aggressive ATL including acute and lymphoma types and chronic types with poor prognostic factors have an extremely poor prognosis, with a median survival of 13 months and overall survival at 3 years of 24% due to resistance to conventional chemotherapy (4, 5). Although new agents have been developed in recent years, the prognosis remains poor. As a result, new therapeutic agents should be created.

The activation of several intracellular signaling molecules is crucial for HTLV-1 oncogenesis. Prior studies indicate that HTLV-1-derived proteins, such as trans-activator X (TAX), and HTLV-1 bZIP factor (HBZ), play central roles in ATL pathogenesis (2). Furthermore, the proliferation of ATL cells is linked to the constitutive activation of the nuclear factor-kappa B (NF-Embedded ImageB) pathway, Janus kinase and signal transducer and activator of transcription proteins (6, 7). Furthermore, NF-Embedded ImageB is caused by a unique HTLV-1 gene, Tax, which has been linked to tumor growth in an in vivo model of ATL (7). In particular, gain-of-function alterations have been found in several molecules involved in the activation of the T-cell receptor (TCR)/NF-Embedded ImageB pathway (8). A conspicuous feature of driver lesions in ATL is their strong enrichment in the elements of TCR/NF-Embedded ImageB signaling and their downstream or associated pathways, accounting for more than 90% of ATL cases (8). In ATL, mutations are often found in downstream signals of TCR/NF-Embedded ImageB, such as phospholipase Cγ1, protein kinase C (PKC)-β, and caspase recruitment domain family member 11 (CARD11) (9). In particular, CARD11 creates a cytoplasmic scaffolding protein that is needed for TCR/NF-Embedded ImageB pathway activation. CARD11 forms a signalosome complex with BCL10 immune signaling adaptor (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) (so-called CBM complex) and functions directly downstream of PKC (10). In ATL, CARD11 mutations are observed in 24% of cases, and CARD11 activation involves multiple mechanisms, including mutations, intragenic deletions and copy number amplifications (9). Therefore, for ATL cells, homeostatic activation of the NF-Embedded ImageB pathway is a requirement for survival, and the advancement of therapeutic agents targeting molecules linked to this pathway is expected.

Dimethyl fumarate (DMF) is a drug authorized by the US Food and Drug Administration and the European Medicines Agency which exhibits multiple effects on cellular signaling, cell death, and proliferation (11-13). DMF is clinically employed as the first-line treatment for relapsing-remitting multiple sclerosis, and as a systemic medication for moderate to severe psoriasis (14, 15). DMF is an activator of nuclear factor-erythroid 2-related factor 2 (16), and promotes apoptosis of activated T-cells (11). In particular, DMF is an efficient inhibitor of NF-Embedded ImageB signaling in activated T-cells and different malignant cells such as melanoma, glioblastoma, cutaneous T-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL) (13, 17, 18). We previously highlighted that DMF inhibits the activation (nuclear translocation) of NF-Embedded ImageB molecules in ATL cells (19). However, the specific mechanism of the inhibitory effect on NF-Embedded ImageB molecules remains unclear. In this research, we show that DMF inhibits activation of the TCR/NF-Embedded ImageB pathway via suppressing the CBM complex.

Materials and Methods

Reagents and antibodies. Sigma–Aldrich supplied the DMF (Tokyo, Japan). Working solutions were developed in RPMI 1640 medium from a stock solution prepared by dissolving in dimethyl sulfoxide (DMSO). Control cells were incubated with DMSO (maximum concentration) only. Antibodies against phospho-inhibitory-kB kinase (IKK)-α/β (Ser176/180) (#2697), BCL10 (#4237), MALT1 (#2496), β-actin (#4967), phospho-CARD11 (Ser652) (#5189), cleaved caspase-3 (#9661), phospho-PKC-βII (Ser660) (#9371), PKC-β (#46809), cellular inhibitor of apoptosis protein-2 (c-IAP2) (#3130), cleaved poly (ADP-ribose) polymerase (PARP) (#9541), stress-activated protein kinase/c-Jun N-terminal kinase SAPK/JNK (#9252) and phospho-SAPK/JNK (Thr183/Try185) (#4668) were acquired from Cell Signaling Technology (Beverly, MA, USA). A dual inhibitor of BCL2 apoptosis regulator (BCL2) and BCL2-like 1 (BCL-xL) navitoclax (ABT-263) was acquired from Selleck Biotech (Tokyo, Japan). Horseradish peroxidase-conjugated secondary antibodies (sc-7074, sc-707692) were acquired from Santa Cruz Biotechnology (Dallas, TX, USA). Primary and secondary antibodies were diluted at 1:1000 and 1:5000, respectively.

Cell lines and culture. The Japanese Collection of Research Bioresources Cell Bank (Tokyo, Japan) provided the MT-2 cell, a human HTLV-1-infected cell line. MT-2 cells were cultured in RPMI 1640 containing 10% fetal bovine serum (FBS) (Hyclone, Logan, UT, USA), 100 u/ml penicillin, 100 μg/ml streptomycin (Life Technologies, Grand Island, NY, USA), and 2 mM of glutamine in an incubator with 5% CO2 at 37°C.

Cell proliferation and cell-cycle assay. Cell viability was determined using trypan blue exclusion assay with a Countess II FL Automated Cell Counter (Thermo Fisher Scientific, Waltham, MA, USA) after cells were cultured in RPMI 1640 medium with 10% FBS in the presence (75 μM) or absence of DMF, navitoclax alone, and DMF plus navitoclax for 48 h, according to the manufacturer’s instructions.

For cell-cycle assay, cells (1×106/ml) were treated in the presence (75 μM) or absence of DMF for 48 h. Then cells were stained with Cell Cycle Assay Solution Blue (Dojindo Laboratories, Kumamoto, Japan) according to the manufacturer’s instructions. The proportion of cells in each phase (sub-G1, G1, S, and G2/M) was assessed with a flow cytometer (FACSCalibur; BD Biosciences, Tokyo, Japan).

Immunoblotting. After being treated with RPMI 1640 supplemented with 10% FBS in the presence (50, 75, and 100 μM) or absence of DMF and 2 μM of navitoclax, the MT-2 cells were washed twice with cold phosphate-buffered saline. Then cell lysates were made using ice-cold RIPA lysis buffer (Santa Cruz Biotechnology) with 5 mM NaF, 0.5 mM sodium orthovanadate, and 1% protease inhibitors, incubated for 30 min at 4°C, and then centrifuged at 9,170 × g for 10 min, while supernatants were kept. The cell lysates were eluted by incubating them for 5 min at 95°C in sodium dodecyl sulfate sample buffer (Bio-Rad Laboratories, Hercules, CA, USA). The samples were stacked into 7-15% Tris-glycine gel (Bio-Rad Laboratories) and transferred to polyvinylidene difluoride membranes (GE Healthcare, Amersham, UK). Next, immunoblotting assays were conducted following the instructions of the manufacturers of the antibodies. Blots were visualized using horseradish peroxidase-conjugated secondary antibodies and enhanced chemiluminescence detection reagent (GE Healthcare, Tokyo, Japan). Membranes were incubated in stripping buffer (Pierce, Rockford, IL, USA) according to the manufacturer’s instructions for re-blotting with other antibodies.

Statistical analysis. Easy R was employed for the statistical analysis of cell-cycle and cell-proliferation assays. The data collected are presented as the mean±standard deviation. Statistical differences between groups were determined using analysis of variance with Bonferroni’s multiple comparison tests after asserting that the data satisfied the assumptions of the statistical test employed. p-Values less than 0.05 were deemed statistically significant.

Results

DMF suppresses phosphorylation of CARD11 and IKKα/β, and expression of BCL10 and MALT1 in MT-2 cells. We previously highlighted that DMF suppressed the NF-Embedded ImageB signaling pathway in HTLV-1-infected MT-2 cells (19). However, the inhibitory mechanism was unknown. To determine the mechanism of action, we initially evaluated the effects of DMF on the CBM complex, which plays a crucial role upstream of NF-Embedded ImageB signaling in MT-2 cells. DMF treatment for 24 h suppressed CARD11 phosphorylation and BCL10 and MALT1 expression in MT-2 cells in a dose-dependent fashion (Figure 1). As expected, phosphorylation of IKKα/β, which is the downstream kinase of the CBM complex, was also inhibited in the same fashion. These outcomes indicate that DMF inhibits CBM complex activity followed by IKKα/β dephosphorylation in MT-2 cells.

Figure 1.
Figure 1.

Dimethyl fumarate (DMF) suppresses phosphorylation of caspase recruitment domain family member 11 (CARD11) and inhibitory-kB kinase (IKK)-α/β, and expression of BCL10 immune signaling adaptor (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) in MT-2 cells. MT-2 cells were treated with dimethyl sulfoxide (DMSO) and DMF at the indicated concentrations for 24 h. Immunoblotting was performed with specific antibodies against pSer176/180-IKKα/β, pSer652-CARD11, BCL10, MALT1, and β-actin. The results are representative of two independent experiments.

DMF suppresses CARD11 phosphorylation in MT-2 cells irrespectively of PKC-β phosphorylation status. We then evaluated whether DMF inhibits PKC-β/θ upstream of CBM complex signaling. As depicted in Figure 2, although CARD11 phosphorylation was inhibited by DMF even at 50 μM, PKC-β phosphorylation was not altered. However, constitutive phosphorylation of PKC-θ was not found in MT-2 cells (data not shown). These outcomes indicate that DMF suppresses CARD11 phosphorylation irrespectively of PKC-β phosphorylation status in MT-2 cells. In other words, DMF may directly suppress the CBM complex in MT-2 cells.

Figure 2.
Figure 2.

Dimethyl fumarate (DMF) suppresses caspase recruitment domain family member 11 (CARD11) phosphorylation irrespective of protein kinase C (PKC)-β phosphorylation status in MT-2 cells. MT-2 cells were treated with dimethyl sulfoxide and DMF at the indicated concentrations for 24 h. Immunoblotting was performed with specific antibodies against pSer660-PKC-βII, PKC-β, pSer652-CARD11, and β-actin. The results are representative of two independent experiments.

DMF induces accumulation of cells in sub-G1 and S-/G2M phases in MT-2 cells. We previously demonstrated that DMF suppresses proliferation and cell death in MT-2 cells (19). We further explored the effects of DMF on the cell-cycle distribution in MT-2 cells (Figure 3). When MT-2 cells were treated with 75 μM of DMF for 48 h, the proportion of G2/M phase cells increased by approximately 30% (p<0.05, Figure 3B). The proportion of sub-G1 phase cells also increased almost three-fold with DMF treatment (p<0.05, Figure 3B). In contrast, the proportion of G1 phase cells decreased by over 30% (p<0.05, Figure 3B). These outcomes imply that DMF leads to cell-cycle arrest at the G2/M phase and cell death in MT-2 cells.

Figure 3.
Figure 3.

Dimethyl fumarate (DMF) induces accumulation of cells in sub-G1 and G2/M phases in MT-2 cells. MT-2 cells (1×106/ml) were cultured in 12-well tissue culture plates treated with dimethyl sulfoxide (DMSO) as a control and 75 μM of DMF for 48 h. The frequency of cells in sub-G1, G1, S, and G2/M phases was measured using flow cytometric analysis with Cell Cycle Assay Solution Deep Red staining. A: Representative cell-cycle histograms of MT-2 cells showing the proportion of cells in sub-G1, G1, S, and G2/M phases. B: Data represent the average of triplicate samples, and error bars represent one standard deviation from the mean for triplicate wells. The results are representative of two independent experiments. *Significantly different from the control at p<0.05 using analysis of variance with Bonferroni multiple comparison test.

Navitoclax modestly enhances DMF-induced suppression of MT-2 cells via inhibition of cIAP-2 expression and phosphorylation of JNK. In prior research, we discovered that DMF inhibited expression of cIAP-2 and survivin but not of BCL2 and BCL-xL in MT-2 cells (19). Therefore, we assessed whether the BCL2/Bcl-xL inhibitor navitoclax promoted an antiproliferative effect on DMF treatment in MT-2 cells. Cells were treated with DMSO alone as a control, 75 μM of DMF, 2 μM of navitoclax, and DMF in combination with navitoclax for 48 h in MT-2 cells. As depicted in Figure 4A, DMF alone and navitoclax alone considerably lowered the number of live cells when compared to the control. Although DMF in combination with navitoclax reduced the number of live cells more than with DMF or navitoclax alone, the effect was modest. We then investigated the effects of these agents on the expression of apoptosis-related proteins in MT-2 cells. As depicted in Figure 4B, PARP and caspase-3 were activated in cells treated with navitoclax alone and with both navitoclax and DMF. Expression of cIAP-2 was lower in cells treated with both DMF and navitoclax than in those treated with either DMF or navitoclax alone. Furthermore, phosphorylation of JNK was more prevalent in cells treated with both DMF and navitoclax than those with DMF alone. These findings indicate that navitoclax modestly improves the antiproliferative effect of DMF at least in part via inhibiting cIAP-2 expression and promoting phosphorylation of JNK in MT-2 cells.

Figure 4.
Figure 4.

Navitoclax enhances dimethyl fumarate (DMF)-induced suppression of MT-2 cells via inhibition of cellular inhibitor of apoptosis protein (cIAP)-2 expression and phosphorylation of c-Jun N-terminal kinase (JNK). MT-2 cells were cultured in 12-well tissue culture plates and treated with dimethyl sulfoxide as a control, 75 μM of DMF, or 2 μM of navitoclax, or 75 μM of DMF plus 2 μM of navitoclax for 48 h. A: Cell viability was measured using trypan blue exclusion assay. Data are expressed as the mean percentage relative to the control cells (C) and are the average of triplicate samples. D: DMF; N: navitoclax. Error bars represent one standard deviation from the mean of the triplicate wells. The results are representative of three independent experiments. *Significantly different at p<0.05 using ANOVA with Bonferroni multiple comparison test. B: Immunoblotting was performed with specific antibodies against cleaved (CL)-poly (ADP-ribose) polymerase (PARP), CL-caspase-3, c-IAP2, pTyr185-JNK, JNK, and β-actin. The results are representative of two independent experiments.

Discussion

In this research, we determined for the first time that DMF inhibits activation of the NF-Embedded ImageB signaling pathway by suppressing the CBM complex in HTLV-1-infected cells. As depicted in Figure 1, DMF suppressed CARD11 phosphorylation, and BCL10 and MALT1 expression in MT-2 cells. However, it suppressed CARD11 phosphorylation irrespective of PKC-β phosphorylation status in MT-2 cells (Figure 2). These outcomes indicate that DMF may directly suppress the CBM complex in MT-2 cells. The NF-Embedded ImageB signaling pathway, among others, is constitutively activated in ATL cells (20). The canonical NF-Embedded ImageB pathway comprises p65 and p50 transcription factors, both of which are kept in the cytoplasm by an inhibitor protein, IEmbedded ImageBα. Phosphorylation of IEmbedded ImageBα by upstream kinases such as IKKα/β influences proteasomal degradation of IEmbedded ImageBα. Thus, p65/p50 molecules can translocate to the nucleus, where they bind to DNA and influence gene transcription (21). The non-canonical NF-Embedded ImageB pathway comprises of avian reticuloendotheliosis viral oncogene-related B (RELB) and p52 transcription factors. This pathway is dependent on phosphorylation-induced p100 processing, which is stimulated by signals from a subset of tumor necrosis factor receptors. The processing of p100 results in the production of p52 and the nuclear translocation of the RELB/p52 heterodimer (22, 23). In a prior report, we indicated that DMF suppressed p65, RELB, and p52 expression in the nucleus in MT-2 cells (19). In other words, we determined that DMF inhibits the nuclear translocation of NF-Embedded ImageB molecules in MT-2 cells. Based on the findings in the present study, there is a possibility that the target of DMF is the CBM complex in ATL cells. Ishikawa et al. recently revealed that MALT1 inhibitor induces apoptosis and suppresses MALT1-mediated NF-Embedded ImageB activation in ATL-derived cells (24). Further study is required to assert whether MALT1 mediates NF-Embedded ImageB inactivation by DMF in ATL cells.

NF-Embedded ImageB is known to function as a pro-survival factor and to contribute to cell death resistance in several hematological malignancies (20-22). In initial reports, DMF was shown to be a potent inhibitor of NF-Embedded ImageB signaling in activated T-cells and different hematological malignant cells such as cutaneous T-cell lymphoma and DLBCL (13, 17). Schmitt et al. showed the mechanism of NF-Embedded ImageB inhibition by DMF in DLBCL. Interestingly, contrary to the results found in ATL cells, DMF did not inhibit the CBM complex downstream of the B-cell receptor but inhibited NF-Embedded ImageB by succinylation of IEmbedded ImageB kinase and JAK kinase (13). This implies that the mechanism of action varies depending on the cell lineage.

Overexpression of anti-apoptotic BCL2 family proteins such as BCL2, BCL-xL, and BCL-w is often linked to cancer resistance to chemotherapy (23). Navitoclax, an orally bioavailable small-molecule mimetic of the BCL2 homology domain 3, particularly inhibits BCL2, BCL-xL, and BCL-w with high affinities (25, 26). Navitoclax has demonstrated broad effects on a panel of human tumor cell lines and has high activities against small-cell lung cancer and acute lymphoblastic leukemia cell lines at half-maximal effective concentration of ~1 μM (26). Previous analysis shows that HTLV-1-associated adult T-cell leukemia cells overexpress BCL2, BCL-xL, and BCL-w, and are highly sensitive to navitoclax (23). Furthermore, the report indicates that the molecular mechanism by which TAX, an HTLV-1 oncogenic protein, increases the expression of BCL2-associated X, apoptosis regulator (BAX), an apoptosis-promoting protein, promotes the therapeutic effect of navitoclax (23). In a prior study, we revealed that DMF did not inhibit protein expression of BCL2 and BCL-xL in MT-2 cells. Therefore, we proposed that the combination of navitoclax and DMF would potentiate the antiproliferative effect in MT-2 cells. As depicted in Figure 4A, the number of MT-2 cells remaining after treatment with both DMF and navitoclax was lower than that with either DMF or navitoclax alone. Expression of cIAP-2 was lower in cells treated with both DMF and navitoclax than those treated with either DMF or navitoclax alone. Furthermore, phosphorylation of JNK was greater in cells treated with both DMF and navitoclax than those treated with DMF alone. These outcomes indicate that navitoclax modestly enhances the antiproliferative effect of DMF at least in part via inhibiting cIAP-2 expression and promoting phosphorylation of JNK in MT-2 cells.

DMF is authorized for the treatment of relapsing forms of multiple sclerosis and psoriasis (14, 15). The only severe and irreversible side-effect described for DMF is progressive multifocal leukoencephalopathy that can be almost totally ruled out by continuous monitoring of blood cell counts (27). This is particularly attractive for the clinical prospects of DMF as a potential medication for ATL.

Overall, DMF inhibits proliferation, and influences apoptosis of HTLV-1-infected cells by suppressing the CBM complex in the NF-Embedded ImageB pathway. It was also revealed that concomitant use of the BCL2/BCL-xL inhibitor navitoclax increased the inhibitory effect of DMF on the proliferation of HTLV-1-infected cells. DMF should be evaluated further as an innovative ATL agent.

Acknowledgements

The Authors thank Ms. Yuki Seki for her technical assistance. We appreciate Enago for English language editing. This study was supported by a research grant (2022) (S.I.) from the Japanese Society of Hematology.

Footnotes

  • Authors’ Contributions

    All Authors performed experiments. T.S. and S.I. designed the research, wrote the article, and discussed the contents of the article.

  • Conflicts of Interest

    The Authors declare no competing financial interests.

  • Received February 8, 2023.
  • Revision received February 26, 2023.
  • Accepted March 13, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Dimethyl Fumarate Suppresses the Proliferation of HTLV-1-infected T Cells by Inhibiting CBM Complex-triggered NF-GraphicB Signaling
TSUYOSHI SATO, TAKAHIRO MAETA, SHIGEKI ITO
Anticancer Research May 2023, 43 (5) 1901-1908; DOI: 10.21873/anticanres.16349
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