Research ArticleExperimental Studies
Open Access

Effects of ERK1/2 Inhibitors on the Growth of Acute Leukemia Cells

MAI ITOH and SHUJI TOHDA
Anticancer Research December 2024, 44 (12) 5263-5270; DOI: https://doi.org/10.21873/anticanres.17354

Abstract

Background/Aim: Extracellular signal-regulated kinases (ERK)1/2 are important regulatory proteins that control cell proliferation and survival, playing a significant role in cancer progression, metastasis, and chemoresistance. This study investigated the effects of ERK1/2 inhibitors on the in vitro growth of acute leukemia cell lines. Materials and Methods: Three ERK1/2 inhibitors were used: SCH772984, temuterkib (LY3214996), and ulixertinib (BVD-523). Four acute myeloid leukemia cell lines (OCI/AML3, HL-60, THP-1, and U-937) and two T-lymphoblastic leukemia cell lines (Jurakt and KOPT-K1) were treated with these inhibitors. Cell growth was assessed using a colorimetric assay, and cell-cycle progression and apoptosis were analyzed using flow cytometry. The expression of intracellular signaling proteins was evaluated via immunoblotting. The effects of small interfering RNA (siRNA)-mediated ERK1/2 knockdown were also evaluated. Results: The inhibitors suppressed the growth of three leukemia cell lines (OCI/AML3, HL-60, and THP-1) harboring neuroblastoma rat sarcoma virus (NRAS) mutations. Growth suppression occurred through G0/G1 arrest in all three cell lines and through apoptosis in OCI/AML3 cells. Immunoblotting demonstrated that these inhibitors suppressed the expression of MYC proto-oncogene, bHLH transcription factor (MYC), in the three cell lines. The additional molecular mechanisms of growth suppression varied depending on the specific inhibitor and cell line. The inhibitors had milder suppressive effects on normal lymphocytes compared to the leukemia cell lines. Conclusion: ERK1/2 inhibitors may serve as novel molecular-targeted drugs for treating leukemia with NRAS mutations.

Key Words:

Acute leukemia is a highly aggressive disease characterized by unlimited proliferation of leukemia cells. The development of effective molecular targeted drugs is desirable but has not been sufficiently established.

Mutations in the rat sarcoma virus (RAS) family are among the most frequent oncogenic mutations, occurring in approximately 30% of all cancers (1). Although these mutations have been known for decades, directly targeting them for treatment has proven challenging due to the absence of a suitable drug-binding pocket. Because it is difficult to directly inhibit RAS, attempts have been made to control tumors by suppressing RAS effector signals. RAS/RAF/MEK/ERK (mitogen-activated protein kinase, MAPK) signaling consists of important regulatory proteins that control cell proliferation and survival, and plays a significant role in cancer progression, metastasis, and chemoresistance. MAPK signaling is considered the most critical pathway among the RAS effector signals, and numerous inhibitors targeting this pathway have been developed. MAPK signaling also plays an important role in the survival of normal cells, and its activity is controlled in a complex manner within a certain range. A feedback mechanism also exists in cancer cells; when MAPK signaling is inhibited, a mechanism to maintain activity is induced, and MAPK is reactivated (2, 3). While MAPK inhibitors can initially block the signaling, the effect is transient, as cancer cells frequently develop resistance to the inhibitors. Thus, clinical trials of MAPK inhibitors have demonstrated limited efficacy (4-6).

ERK1/2 is activated through MAPK signaling, which transmits signals downstream from receptor tyrosine kinases (RTKs). Among the MAPK signaling pathways, ERK1/2 exerts a pivotal function, and the direct inhibition of activated ERK1/2 induced by RAS gene mutations is considered a promising target for the treatment of a variety of tumor types with MAPK pathway alterations (7, 8).

This study investigated the effects of the direct ERK1/2 inhibitors, SCH772984 (9), temuterkib (LY3214996) (9, 10), and ulixertinib (BVD-523) (11, 12) on the in vitro growth of human acute leukemia cell lines. We revealed that these inhibitors reduced the proliferation of acute leukemia cell lines harboring Neuroblastoma Rat Sarcoma Virus (NRAS) mutations by inducing cell-cycle arrest and partial apoptosis.

Materials and Methods

Cell lines and cell cultures. Four acute myeloid leukemia cell lines (OCI/AML3, HL-60, THP-1, and U-937) and two T-cell acute lymphoblastic leukemia (T-ALL) cell lines (Jurkat and KOPT-K1) were used. OCI/AML3, HL-60, and THP-1 cells possess NRAS mutations. OCI/AML3 cells were derived from acute myelomonocytic leukemia cells at the Ontario Cancer Institute. HL-60 and U-937 cells were acquired from the Japanese Collection of Research Bioresources (JCRB Cell Bank, Osaka, Japan). THP-1 and Jurkat cells were purchased from the European Collection of Authenticated Cell Cultures (ECACC, Salisbury, UK). KOPT-K1 cells were provided by Drs. Harashima and Orita (Fujisaki Cell Center, Okayama, Japan).

Normal lymphocytes from two healthy volunteers (who provided written informed consent) were used as controls. This study was approved by the Medical Research Ethics Committee of Institute of Science Tokyo (approval number: M2000-818).

Cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum at 37°C in a humidified atmosphere with 5% CO2. All experiments were repeated at least three times to ensure reproducibility.

ERK1/2 inhibitors. Three small-molecule compounds, SCH772984, temuterkib (LY3214996), and ulixertinib (BVD-523), were used as ERK1/2 inhibitors. SCH772984 is a selective ATP-competitive ERK1/2 inhibitor. Temuterkib and ulixertinib inhibit ERK1/2 protein kinase activity, thereby preventing the activation of ERK1/2-mediated signal transduction pathways. The ERK1/2 inhibitors were purchased from Selleck Chem (Houston, TX, USA) and dissolved in dimethyl sulfoxide (DMSO) to a final concentration of 10 mM.

Cell growth assay. Short-term cell growth was evaluated using a colorimetric water-soluble tetrazolium 8 (WST-8) assay kit (Dojindo Laboratories, Kumamoto, Japan) as we previously reported (13). Cells were cultured with increasing concentrations of ERK1/2 inhibitors or co-transfected with siRNAs targeting ERK1 and ERK2. After 72 h of culture, the WST-8 reagent was added, and the optical density (OD) was measured using an enzyme-linked immunosorbent assay plate reader (Multiskan FC, Thermo Fisher Scientific, Waltham, MA, USA). Relative cell proliferation was evaluated as the percentage of the mean OD normalized to that of control cells cultured with the vehicle (DMSO). To examine the effects of each inhibitor on cell morphology and apoptosis, cells cultured for 72 h were harvested and prepared using Cytospin 4 (Shandon, Cheshire, UK). Wright’s stain preparations were then observed under an optical microscope.

Antibodies. Antibodies against p-ERK1/2 (#4370), ERK1/2 (#4695), p-ribosomal S6 kinase (RSK) (#9346), RSK (#9355), dual-specificity protein phosphatase 4 (DUSP4) (#5149), MYC (#13987), p-signal transducer and activator of transcription 1 (STAT1) (#9167), STAT1 (#14994), p-STAT3 (#9145), STAT3 (#12640), cleaved caspase-3 (#9664), cleaved poly (ADP-ribose) polymerase (PARP) (#5625), p27 (#3686), p21 (#2947), cyclin D3 (#2936), horseradish peroxidase (HRP)-conjugated anti-rabbit IgG (#7074), and anti-mouse IgG (#7076) were purchased from Cell Signaling Technology (CST, Danvers, MA, USA). Antibodies against ERK1 (#sc-271269) and ERK2 (#sc-81457) were obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA), while glyceraldehyde-3-phosphate dehydrogenase (GAPDH) antibody (#016-25523) was sourced from FUJIFILM Wako Pure Chemical (Osaka, Japan).

Immunoblotting analysis. The effects of ERK1/2 inhibitors and siRNAs on protein expression and phosphorylation were examined via immunoblotting. Cells treated with inhibitors for 24 h or co-transfected with siRNAs targeting ERK1 and ERK2 for 48 h were harvested and lysed. Lysates were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and electrotransferred onto polyvinylidene difluoride membranes. The membranes were incubated in 5% non-fat dry milk for 1 h and probed with primary antibodies and horseradish peroxidase (HRP)-conjugated secondary antibodies. Immunoreactive bands were detected using the Pierce Enhanced Chemiluminescent Western Blotting Substrate (Pierce Biotechnology, Rockford, IL, USA).

Cell-cycle analysis and apoptosis assay. Cells treated with ERK1/2 inhibitors for 48 h were stained with propidium iodide (PI) to evaluate the cell cycle, and with annexin V-fluorescein isothiocyanate (FITC) and PI to examine apoptosis. The stained cells were analyzed using a FACSCalibur cytometer (BD Biosciences, Franklin Lakes, NJ, USA).

siRNA-mediated ERK1/2 knockdown. To confirm the specificity of the effects of ERK1/2 inhibitors, we performed siRNA-mediated ERK1/2 knockdown. Three different pre-designed siRNAs (Stealth siRNAi™) targeting ERK1 (HSS108538 [5′-GGAAGCCAUGAGAGAUGU CUACAUU-3′], HSS108539 [5′-GCAUUCUGGCUGAGAUGCU CUCUAA-3′], and HSS108540 [5′-CCUGCUGGACCGGAUGUU AACCUUUU-3′]), and ERK2 (HSS108535 [5′-GCCGAAGCACC AUUCAAGUUCGACA-3′], HSS108536 [5′-UCACACAGGGUUCC UGACAGAAUAU-3′], and HSS10 8537 [5′-GGGCUACACCAA GUCCAUUGAUAUU-3′]), and a negative control Duplex were transfected with 40 nM of each siRNA using the Neon™ pipette tip chamber-based electroporation system (Life Technologies, Carlsbad, CA, USA) according to the manufacturer’s instructions. Thereafter, the cells were immediately transferred to the culture medium.

Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cells co-transfected with ERK1 and ERK2 siRNAs were cultured for 48 h, and mRNA expression of ERK1 and ERK2 was measured using RT-qPCR with FastStart Essential DNA Green Master Mix (Roche Diagnostics, Mannheim, Germany) and ERK1- and ERK2-specific primers (QuantiTect Primer Assay QT02589321 and QT00065933, respectively; Qiagen, Hilden, Germany). Relative expression of ERK1 or ERK2 mRNA was determined after normalization to GAPDH mRNA (Qiagen).

Statistical analysis. The statistical significance of the differences in cell growth was evaluated using Student’s t-test, with p-values less than 0.01 considered significant.

Results

Effects of ERK1/2 inhibitors on cell growth. Treatment with SCH772984, temuterkib, and ulixertinib markedly suppressed the growth of three NRAS-mutated cell lines (OCI/AML3, HL-60, and THP-1) in a dose-dependent manner, whereas no suppression was observed in the three cell lines without NRAS mutations (U-937, Jurkat, and KOPT-K1) (Figure 1, upper panels). The suppressive effects of each inhibitor on normal lymphocytes were milder than those on the NRAS-mutated leukemia cell lines (Figure 1, lower panels).

Figure 1.
Figure 1.

Effects of ERK1/2 inhibitors on the growth of leukemia cells and normal lymphocytes. The inhibitors were added to leukemia cell lines (upper panel) and normal lymphocytes (lower panel) for 72 h to assess dose response. Cell growth was evaluated in a colorimetric assay and the results were expressed as the percentage of the mean optical density in the inhibitor-treated cells relative to that in DMSO-treated control cells; *p<0.01 compared to control.

Analysis of cytospin preparations indicated that treatment with the three ERK1/2 inhibitors resulted in disruption of the cell membrane and the partial appearance of apoptotic cells with nuclear condensation and apoptotic bodies in the three cell lines harboring NRAS mutations, suggesting the induction of apoptosis (Figure 2).

Figure 2.
Figure 2.

Morphological changes of leukemia cells treated with ERK1/2 inhibitors. Cells were cultured with the inhibitors for 72 h and their cytospin preparations were dyed with Wright’s stain and observed under a microscope.

Cell-cycle changes following treatment with ERK1/2 inhibitors. To examine the effects of ERK1/2 inhibitors on cell-cycle progression, we performed cell-cycle assays. Treatment with ERK1/2 inhibitors affected the cell cycle and induced G0/G1 arrest in three cell lines with NRAS mutations (representative data from OCI/AML3, HL-60, and THP-1 cells are shown in Figure 3).

Figure 3.
Figure 3.

Cell-cycle changes in leukemia cells treated with ERK1/2 inhibitors. Cells were treated with the inhibitors at the indicated concentrations for 48 h, stained with propidium iodide, and analyzed for cell-cycle progression using flow cytometry. Representative data from OCI/AML3, HL-60, and THP-1 cells.

Effects on apoptosis induction following treatment with ERK1/2 inhibitors. To evaluate the effects of ERK1/2 inhibitors on the induction of apoptosis, we performed apoptosis assays. Treatment with ERK1/2 inhibitors increased the number of cells both in early apoptosis (annexin V-positive/PI-negative) and in late apoptosis (annexin V-positive/PI-positive) only in OCI/AML3 cells, indicating apoptosis induction. Representative data from OCI/AML3, HL-60, and THP-1 cells are shown in Figure 4.

Figure 4.
Figure 4.

Apoptosis induction in leukemia cells treated with ERK1/2 inhibitors. Cells were cultured with the inhibitors at the indicated concentrations for 48 h, stained with annexin V-fluorescein isothiocyanate and propidium iodide (PI), and analyzed for apoptosis using flow cytometry (A). The bar graph shows the percentage of cells in early (annexin V-positive/PI-negative) and late apoptosis (annexin V-positive/PI-positive) (B). Representative data from OCI/AML3, HL-60, and THP-1 cells.

Effects of ERK1/2 inhibitors on signaling proteins. To investigate the mechanism of growth suppression by the ERK1/2 inhibitors, the expression and phosphorylation of various signaling proteins were examined via immunoblotting (Figure 5). Of the three inhibitors, only SCH772984 reduced ERK1/2 phosphorylation, while temuterkib and ulixertinib inhibited ERK1/2 function without affecting protein expression. Treatment with the three ERK1/2 inhibitors suppressed the phosphorylation of RSK, an ERK1/2 downstream target, which was used to determine ERK1/2 inhibitor efficacy. These inhibitors also down-regulated the expression of DUSP4, a negative regulator of ERK1/2 signaling. The inhibitors suppressed the expression of MYC in the three NRAS-mutated cell lines, and induced cleavage of caspase-3 and PARP (a downstream molecule of caspase-3), indicating apoptosis induction in OCI/AML3 and HL-60 cells.

Figure 5.
Figure 5.

Effects of ERK1/2 inhibitors on signaling proteins in leukemia cells. Cells were cultured with ERK1/2 inhibitors at the indicated concentrations for 24 h and analyzed for the expression of the indicated proteins using immunoblotting.

Effects of ERK1/2 knockdown on cell proliferation and signaling proteins. To confirm the specificity of ERK1/2 inhibitors, ERK1/2 knockdown experiments with siRNAs were performed. Among the three ERK1- and ERK2-specific siRNAs, HSS108539 and HSS108536 most effectively suppressed ERK1 and ERK2 mRNA expression, as assessed using RT-qPCR. Suppression rates for ERK1 mRNA were 29%, 25%, and 33% in OCI/AML3, HL-60, and THP-1 cells, respectively, and 27%, 25%, and 26% for ERK2 mRNA, respectively. Their effects on cell growth and signaling proteins were investigated in detail. Both siRNAs for ERK1 and ERK2 were co-transfected, and cell growth was assessed 72 h after siRNA transfection. The growth rates of the OCI/AML3, HL-60, and THP-1 cells were significantly suppressed (Figure 6A). Knockdown of ERK1 and ERK2 suppressed the expression of ERK1 and ERK2 proteins, respectively (Figure 6B), suppressed the phosphorylation of RSK, expression of DUSP4, MYC, and cyclin D3, and induced the cleavage of caspase-3 and PARP, similar to treatment with ERK1/2 inhibitors. This indicates that the effects of ERK1/2 inhibitors are specific to ERK1/2.

Figure 6.
Figure 6.

Effects of ERK1 and ERK2 knockdown on the cell proliferation and signaling protein expression. (A) Cells were co-transfected with ERK1 and ERK2 siRNA or control siRNA and analyzed for cell growth after 72 h using a colorimetric assay. (B) Signaling proteins were analyzed after co-transfection with ERK1 and ERK2 siRNA for 48 h using immunoblotting. *p<0.01 compared to control.

Discussion

ERK1/2 has been considered a potential target for cancer treatment. Therefore, we investigated the mechanisms of action of these inhibitors in leukemia cell lines. In the present study, we showed that ERK1/2 inhibitors suppress the growth of acute leukemia cell lines harboring NRAS mutations at a concentration that does not significantly affect normal lymphocytes. This suggests that these ERK1/2 inhibitors could be novel molecular-targeted drugs for patients with NRAS-mutated acute leukemia. Growth suppression was mainly caused by G0/G1 arrest in the cell cycle and partially by the induction of apoptosis.

Figure 7 summarizes the molecular mechanisms underlying the inhibitory effects of these inhibitors. The mechanisms through which these three inhibitors suppress ERK1/2 differ. SCH772984 is an ATP-competitive inhibitor of ERK1/2. Temuterkib and ulixertinib inhibit ERK1/2-mediated signal transduction without altering protein expression, thereby preventing the activation downstream pathways. In this study, immunoblotting revealed that treatment with SCH772984 suppressed ERK1/2 phosphorylation, whereas temuterkib and ulixertinib did not. In addition, previous reports have shown that administration of MAPK inhibitors leads to reactivation of ERK1/2 and induces drug resistance (2, 3). In our study, the reactivation of ERK1/2 was not significant, and suppression of phosphorylated RSK, an ERK1/2 downstream target, was used to determine ERK1/2 inhibitor efficacy. This indicated that ERK function was suppressed. The inhibitors also down-regulated the expression of DUSP4, a negative regulator of ERK1/2 signaling, owing to a reduction in ERK1/2 activation.

Figure 7.
Figure 7.

Schematic representation of the molecular mechanism associated with ERK1/2 inhibitors, and the results obtained in this study.

Immunoblotting demonstrated that the inhibitors suppressed MYC expression in three cell lines with NRAS mutations, which may have led to cell cycle arrest. While a previous study showed that SCH772984 treatment induced S-phase arrest in the cell cycle (14), our findings demonstrated that it caused G0/G1-phase arrest, leading to suppressed cell growth. This result is similar to the mechanism of growth suppression in acute lymphoblastic leukemia cell lines by the combination of ERK2 and STAT3 inhibitors (15).

Study limitations. First, only cell lines were used in this experiment. Therefore, experiments using leukemia cells from patients are required to generalize our findings. Second, the flow cytometry assay and intracellular protein expression were examined only 48 h after exposure to inhibitors. Flow cytometry analysis revealed an increase in annexin V-positive cells only in OCI/AML3 cells following inhibitor treatment, and immunoblotting confirmed PARP cleavage, a downstream marker of caspase-3, in both OCI/AML3 and HL-60 cells. However, Wright’s staining showed the appearance of apoptotic cells with nuclear condensation and apoptotic bodies in all three NRAS-mutated cell lines after 72 h of inhibitor treatment. Because we did not examine annexin V-positive cells or protein expression at different time points, potential additional findings may have been overlooked. Third, the mRNA expression after treatment with inhibitors was not evaluated in this study. Therefore, it is not known whether the decrease in protein levels induced by the inhibitors is due to a decrease in mRNA expression or protein degradation. These issues should be addressed in future studies.

Conclusion

We demonstrated that ERK1/2 inhibitors are potential molecular-targeted drugs against leukemia cells, particularly those harboring NRAS mutations, although the molecular mechanisms vary by inhibitor and cell line. Therefore, a thorough investigation of the on- and off-target effects should be performed in pre-clinical studies. Moreover, drug sensitivity tests should be developed to predict treatment outcomes.

Footnotes

  • Authors’ Contributions

    MI and ST designed the study. MI performed the analysis. MI and ST wrote the article.

  • Conflicts of Interest

    The Authors declare no conflicts of interests regarding this study.

  • Funding

    This study was funded in part by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (No. 20K07780).

  • Received October 9, 2024.
  • Revision received October 20, 2024.
  • Accepted October 21, 2024.

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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Effects of ERK1/2 Inhibitors on the Growth of Acute Leukemia Cells
MAI ITOH, SHUJI TOHDA
Anticancer Research Dec 2024, 44 (12) 5263-5270; DOI: 10.21873/anticanres.17354
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