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. 2024 May 27;40(4):629–637. doi: 10.1007/s12288-024-01773-3

CSE1L Silencing Enhances Cytarabine-mediated Cytotoxicity in Acute Myeloid Leukemia

Xiaoyu Liu 1,#, Lin Yang 1,#, Kunping Guan 2,✉, Zhen Chen 1, Hua Yang 1
PMCID: PMC11512944  PMID: 39469152

Abstract

Purpose

This study aims to investigate the increased toxicity of Cytarabine (Ara-c) by knockdown of chromosome segregation 1-like (CSE1L) in acute myeloid leukemia(AML) cells(Kasumi-1, U937, and THP-1 cells) and to explore its possible mechanisms.

Methods

Target gene silencing was achieved using the shRNA-mediated lentivirus method. Apoptosis was identified using the Annexin V PE/7-AAD double-staining assay. Cell viability was assessed with the Cell Counting Kit-8 (CCK-8) assay. Protein expression was detected by Western blotting.

Results

In vitro, knocking down CSE1L promoted caspase-3 and caspase-9 proteins expression and induced apoptosis in AML cells. Knockdown of CSE1L enhanced AML cells' sensitivity to Ara-c. knockdown of CSE1L reduced the expression levels of p-JKA2 and p-STAT3 proteins, while no significant difference was observed in the expression levels of total JAK2 and STAT3 proteins. Furthermore, JAK2 overexpression reversed the increase in Ara-c toxicity to AML cells caused by CSE1L knockdown.

Conclusion

In conclusion, our study reveals that CSE1L is a potential therapeutic target for overcoming Ara-c resistance in AML cells. Thus, we have gained new insights into the oncogenic process of CSE1L in AML cells and raised the prospect of knockdown of CSE1L in AML in combination with cytarabine-targeted therapy.

Keywords: AML, Apoptosis, Ara-c, CSE1L

Introduction

Acute myeloid leukemia (AML), a class of highly prevalent and aggressive hematologic malignancies, is characterized by uncontrolled expansion of immature myeloid cells coupled with a differentiation blockage [1]. Cytarabine (Ara-c), a cell cycle-specific pyrimidine analog sensitive to S-phase cells, has become the principal chemotherapeutic drug for the treatment of AML in recent years due to its ability to limit myeloid cell growth and its quick action without causing harm to normal cells [2, 3]. Despite the intense killing potential of certain genotoxic medications such as Ara-c, cancer cells tend to buffer drug-induced DNA damage through their innate DNA repair ability, resulting in a 5-year survival rate for tumor patients ranging between 5 and 65% [4, 5]. Supplementation with conventional doses of cytarabine has been reported to result in remission rates of more than 70% in AML, yet more than 60% of AML patients relapse [6]; intensive treatment with supplementation with high doses of Ara-c can improve overall survival and reduce relapse rates in AML patients by overcoming the multidrug resistance (MDR) effect and prolonging remission after chemotherapy, but also increased side effects of the drugs, including myelosuppression, hypertriglyceridemia and muscle pain, hence the frequent clinical use of Ara-c combinations [7]. It is thus clear that improving the sensitivity of Ara-c is a major challenge in the clinical management of AML, Finding new combination therapies that enhance the cytotoxicity of cytarabine is extremely important for the prognosis and quality of life of AML patients.

Studies have shown that many molecular targets are associated with leukemia progression and drug resistance [8]. With the advent of various emerging assays, research into the role of these molecular targets in the diagnosis, prognosis, monitoring and targeted treatment of AML has become increasingly topical [9, 10]. In recent years, investigators have noted that combining specific small-molecule inhibitors with standard chemotherapeutic agents for AML may be an ideal therapeutic option [11]. Chromosome segregation 1-like (CSE1L) is a small molecule that is highly expressed in a variety of solid tumours including gastric, colorectal and lung cancers [12–14]. In addition, CSE1L is also involved in a variety of cellular functions, including cell proliferation, cycling, apoptosis, and tumor projection [15–17]. CHUN-CHAO CHANG et al. showed that high CSE1L expression levels correlate with the malignancy of colorectal cancer(CRC), in which reduced CSE1L expression in CRC cells may hinder proliferation or improve cancer outcomes [18]. However, the role of CSE1L in cytotoxicity of Ara-c is unclear. In this study, we used AML cells (U937, THP-1, Kasumi-1 cells) as a model to investigate the effects of knockdown of CSE1L on the apoptosis and activity of AML cells and their sensitivity to cytarabine, with a view to providing a theoretical basis and experimental rationale for improving the efficacy of Ara-c.

Materials and Methods

Cell Cultures

AML cell lines U937, THP-1 and Kasumi-1 are routinely stored in our laboratory. AML cells were cultured in RPMI-1640 medium(Gibco Company Grand Island, NY, USA) with 10% fetal bovine serum(FBS) and 1% penicillin and streptomycin( Punosai, Wuhan, China) in an incubator at 37 °C, 5% CO2 and 85% humidity. The investigation involved interfering with AML cells using Ara-c(aladdin, Shanghai, China) at dosages of 0, 0.1, 0.5, 1, 2, and 4 μM.

Cellular Infection

The specific interfering CSE1L lentivirus (sh-CSE1L) and empty vector lentivirus (sh-NC) were provided by Han Hang Seng (Shanghai, China). The lentiviral vector of RNA interference-mediated gene silencing is HBLV-h-shRNA-CSE1L1-ZsGreen-PURO.The empty vector of lentivirus in negative control is HBLV-h-ZsGreen-PURO NC. AML cells were infected with the lentivirus for 72 h and then screened by adding a concentration of puromycin(Solarbio, Beijing, China) until the infection efficiency was above 90%. Subsequent concentrations of puromycin were halved and the culture was maintained. The infected cells that had been stabilized were used in future studies.

CCK-8 Assay for Cell Viability

Cell Counting Kit-8(CCK-8) assay was carried out to measure the viability of Kasumi-1, U937 and THP-1 cells. The AML cells(8 × 10^3 cells/well) were seeded on 96-well plates and incubated with Ara-c (0, 0.1, 0.5, 1, 2, 4 μM). After incubation for 24 h, cells were incubated with cck-8 solution(10 μL) for 2 h. After that, the absorbance values of each well were measured at 450 nm using a multifunctional enzyme marker(Bio Tek, USA). The 50% inhibitory concentration (IC50) was calculated by SPSS 26.0(IBM, New York, USA).

Western Blot Analysis

AML cells(1 × 10^6 cells) were collected and the cells were lysed using RIPA strong lysis solution. The protein content of the lysates was determined using the BCA method. The standard sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) method was applied to separate the proteins. Then, the gels were transferred, blocked, and cultured with primary antibodies against the following: CSE1L(ab189180, Abcam, USA), P-JAK2/JAK2(Y1007 + Y1008)(Abmart, Shanghai, China), P-STAT3/STAT3(Tyr705)(Abmart, Shanghai, China), caspase-3(Wanlei, Shenyang, China) and caspase-9(Wanlei, Shenyang, China). β-actin(Boster, Wuhan, China) was used as the internal control. After incubating the membranes with HRP-goat Anti-rabbit IgG secondary antibodies(Boster, Wuhan, China) for 1 h at room temperature. The bands were detected by the FluorChem HD2 gel imaging analysis system(ProteinSimple, USA).

Annexin V PE/7-AAD Double-staining Assay for Apoptosis Detection

Annexin V-PE/7-AAD double-staining assay (Solarbio, Beijing, China) was carried out to measure the apoptosis of Kasumi-1, U937 and THP-1 cells. AML cells(1 × 10^6 cells/well) were fixed with 5 µL Annexin V/PE solution at room temperature for 5 min in the dark. Then, 10 µL of 7-AAD solution and 400 µL of PBS were added. Apoptosis was subsequently analyzed on a flow cytometer(Beckman, Germany).

Bioinformatics Analysis

The GEPIA database is an online website, and its analyzed tumor and normal tissue data were from the TCGA database [19]. The GEPIA database (http://gepia2.cancer-pku.cn/#analysis) was used to explore the correlation of CSE1L with JAK2 and STAT3. Screening conditions: gene A: CSE1L, gene B: STAT3 or JAK2, Correlation Coefficient: Pearson, Cancer name: LAML Tumor, GTEx: Whole Blood. p < 0.05 was considered a statistically significant difference.

Statistical Analysis

Statistical analysis of the data was analyzed using SPSS 26.0(IBM, New York, USA). Graphs drawing were made using GraphPad Prism 8(GraphPad Prism, San Diego, CA, USA). Protein bands were analysed for grey scale values using Image J(NIH, Bethesda, USA). Statistical analyses were performed using student's t-test or one-way analysis of variance. Data are expressed as mean ± standard deviation (SD). Pearson correlation analysis was used between two genes. p < 0.05 was considered significant.

Results

Knockdown of CSE1L Promotes Cell Apoptosis

Multiple AML cell lines (Kasumi-1, U937, and THP-1) expressed CSE1L protein (Fig. 1A-C). We were able to significantly inhibit the protein expression in these cell lines using CSE1L shRNA and evaluated the functional implications of this inhibition. After CSE1L shRNA knockdown, densitometry analysis of protein bands in arbitrary units was significant in all three cell lines(p < 0.05). We used flow cytometry to detect the apoptosis of each group. As shown below(Fig. 1D-F), in Kasumi-1, U937 and THP-1 cells, the apoptosis was significantly higher in the sh-CSE1L group compared to sh-NC group(p < 0.05). These data suggest that CSE1L knockdown promotes apoptosis in AML cells.

Fig. 1.

Fig. 1

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Knockdown of CSE1L induces apoptosis in AML cells. (A-C) Western blot assessment of CSE1L protein expression levels in Kasumi-1, U937 and THP-1 cells in sh-CSE1L and sh-NC groups. (D-F) flow cytometry assessment of the effect of knockdown of CSE1L on apoptosis in these three cells

Knockdown of CSE1L Promotes Upregulation of Caspase-3 and Caspase-9 Protein Expression

To further evaluate the effect of knockdown of CSE1L on apoptosis in AML cells, the changes in caspase-3 and caspase-9 protein expression levels in different groups of Kasumi-1, U937 and THP-1 cells were observed by Western blot in this experiment. As shown below(Fig. 2A-C), caspase-3 and caspase-9 protein expression levels were significantly higher in the sh-CSE1L group of AML cells compared to the sh-NC group(p < 0.05). These data suggest that knockdown of CSE1L promotes upregulation of caspase-3 and caspase-9 protein expression.

Fig. 2.

Fig. 2

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The effect of CSE1L knockdown on Caspase-3 and Caspase-9 proteins. (A-C) Western blot assessment of the effect of CSE1L knockdown on caspase-3 and caspase-9 proteins expression in Kasumi-1, U937 and THP-1 cells. *p < 0.05,**p < 0.01,***p < 0.001

Knockdown of CSE1L Enhances the Sensitivity of Ara-c to AML Cells

AML cells were cultured with different concentrations of Ara-c(0, 0.1, 0.5, 1, 2, 4 μM) for 24 h. Figure 3A showed that the activity of AML cells reduced significantly with increasing concentration of Ara-c in a concentration-dependent manner. Based on the experimental results, 1 μM Ara-c was selected for further validation in subsequent experiments. Knockdown of CSE1L decreased the IC50 for Ara-C in Kasumi-1, U937 and THP-1 cells(Fig. 3B). we found that CSE1L knowdown resulted in the reduction of cell viability, and enhanced Ara-c-caused the reduction of viability in Kasumi-1, U937 and THP-1 cells (Fig. 3C). Furthermore, knockdown of CSE1L resulted in the increment of apoptosis, enhanced Ara-c-caused the increment of apoptosis in Kasumi-1, U937 and THP-1 cells(Fig. 3D-F).

Fig. 3.

Fig. 3

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Effect of CSE1L knockdown on Ara-C cytotoxicity in AML cells. (A) The viability of Kasumi-1, U937 and THP-1 cells after treatment with different concentrations of Ara-c (0, 0.1, 0.5, 1, 2, or 4 μM) for 24 h. (B) The IC50 values of Ara-c were calculated after treating sh-NC and sh-CSE1L groups of Kasumi-1, U937 and THP-1 cells with different concentrations of Ara-c (0, 0.1, 0.5, 1, 2, 4 μM) for 24 h, respectively. (C) Cell viability was calculated after 24 h of treatment with 1 μM Ara-c in different groups of Kasumi-1, U937 and THP-1 cells. (D-F)The apoptosis was calculated after 24 h of treatment with 1 μM Ara-c in different groups of Kasumi-1, U937 and THP-1 cells. *p < 0.05, **p < 0.01, ***p < 0.001

Knockdown of CSE1L Inhibits the JAK2/STAT3 Pathway

Previous experiments have well illustrated that CSE1L is involved in AML apoptosis. Some researchers have pointed out that the JAK2/STAT3 signaling pathway is closely related to tumor cell apoptosis [20]. Interestingly, we noted from the GEPIA database that CSE1L was positively correlated with JAK2 in AML (r = 0.69, p < 0.001), and CSE1L was positively correlated with JAK2 (r = 0.27, p < 0.001) (Fig. 4A). Therefore, we hypothesized that in AML cells, the interaction of CSE1L with JAK2 and STAT3 induced altered cellular phenotypes. To confirm the above speculation, we chose the U937 cell model for subsequent validation in combination with the results of the previous experiments. As shown in the figure below, knockdown of CSE1L reduced the expression levels of p-JKA2 and p-STAT3 proteins, while no significant difference was observed in the expression levels of total JAK2 and STAT3 proteins(Fig. 4B). The results suggest that knockdown of CSE1L may act on AML cells by inhibiting the activity of JAK2/STAT3 signaling pathway.

Fig. 4.

Fig. 4

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Effect of knockdown of CSE1L on the JAK2/STAT3 signaling pathway. (A) Bioinformatics analysis of CSE1L correlation with JAK2 and STAT3 in AML. (B) Western blot assay to assess the effect of CSE1L knockdown on the JAK2/STAT3 signaling pathway. *p < 0.05, **p < 0.01, ***p < 0.001

JAK2 Overexpression Attenuates the Effect of CSE1L on Cytotoxicity of Ara-c

To further investigate the role of the JAK2/STAT3 signaling pathway, we next evaluated the effect of JAK2 overexpression on the cytotoxicity of Ara-c. We used different concentrations of IL-6(0, 1, 5, 10, 20, 40, or 80 ng/mL) on U937 cells for 24 h. The activity of U937 cells showed different degrees of enhancement, peaking at a concentration of 5 ng/mL (Fig. 5A). Therefore, we used a concentration of 5 ng/mL of IL-6 for subsequent experiments. Figure 5B showed that IL-6 induces JAK2 overexpression. JAK2 overexpression reversed the increase in Ara-c toxicity to U937 cells caused by CSE1L knockdown(Fig. 5C).

Fig. 5.

Fig. 5

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Effect of JAK2 overexpression on cytotoxicity of Ara-C. (A) U937 cells were treated with different concentration of IL-6(0, 1, 5, 10, 20, 40, or 80 ng/mL) for 24 h. (B) Western blot to assess the expression of JAK2 protein in different treatment groups. (C) Apoptosis in different groups of cells treated with 5 ng/mL IL6 for 24 h. *p < 0.05, **p < 0.01, ***p < 0.001

Discussion

CSE1L was first identified in breast cancer, where it plays an important role in maintaining the balance between cell proliferation and apoptosis [21]. CSE1L is now shown to be significantly expressed in a range of solid cancers. Luo et al. showed that CSE1L was highly expressed in patients with nasopharyngeal carcinoma. Overexpression of CSE1L in human nasopharyngeal carcinoma 5–8 F and SUE-1 cells promotes cell proliferation, migration and invasion, and reduces apoptosis. Knockdown of CSE1L decreased proliferation and increased apoptosis in nasopharyngeal carcinoma cells [22]. Liu et al. demonstrated that CSE1L expression was elevated in lung cancer tissues. Knockdown of CSE1L inhibited the proliferation of lung cancer cells, blocked the cell cycle and induced apoptosis [14]. However, the function of CSE1L in AML needs additional exploration. To this end, we used the AML cells(Kasumi-1, U937 and THP-1) as models to construct CSE1L-targeted knockdown lentivirus and infected Kasumi-1, U937 and THP-1 cells to form a stable knockdown CSE1L cell line. In this study, we found that knockdown of CSE1L induced apoptosis in AML cells. It is well known that apoptosis is biologically important for cell differentiation, proliferation and organismal development [23, 24]. It follows that CSE1L knockdown may be helpful in the treatment of AML patients. In support of this idea, we noted that several apoptotic factors in the caspase family are involved in apoptosis, but caspase-3 and caspase-9 are the most important in the activation of caspases driven by mitochondrial apoptosis [25]. Multiple studies have shown that caspase-3 and caspase-9 activation in apoptosis is closely associated with the development of AML [26, 27]. The results of this study showed that CSE1L knockdown in AML cells caused an increase in caspase-3 and caspase-9 protein expression levels, which resulted in apoptosis. The above results further confirm that CSE1L is correlated with the development of AML.

However, resistance (resistance that occurs during or after treatment) in AML cells has become a major obstacle to the treatment of AML with Ara-c [28]. In recent years, more and more researchers have focused on new inhibitors that can increase the sensitivity of Ara-c. Qin et al. found that OGG1 expression was significantly higher in AML samples than in normal samples, both by bioinformatics analysis of the GEPIA database and by experiments with clinical samples. When OGG1 was downregulated, the sensitivity of leukemic cells to cytarabine was increased [29]. Zhang et al. found that the IC50 value of cytarabine in AML cells was positively correlated with NONO protein levels. Silencing of NONO significantly increased the sensitivity of AML cells to agranulocytosis, while overexpression of NONO significantly decreased the sensitivity of AML cells to agranulocytosis [30]. Consistent with the results of other scholars, the present study also found that CSE1L knockdown significantly decreased the IC50 of AML cells to agranulocytosis and significantly increased the apoptosis rate under agranulocytosis treatment conditions. The results suggest that inhibition of CSE1L can improve the sensitivity of AML cells to Ara-c.

To date, the molecular mechanism of action of CSE1L in AML is unclear. Lei et al. showed that inhibition of the JAK2/STAT3 signaling pathway in AML reduced the tumorigenicity of AML [31]. mesbahi et al. showed that blocking the JAK2/STAT3 signaling pathway reduced the tumorigenic activity of AML cells [32]. To investigate whether CSE1L acts on AML cells through the JAK2/STAT3 signaling pathway, our group used U937 cells as a model to investigate the mechanism of CSE1L action in AML. In this study, we found that the expression levels of p-JAK2 protein and p-STAT3 protein decreased in AML cells with CSE1L knockdown, while the total expression levels of JAK2 protein and STAT3 protein were not significantly changed. When the JAK2 agonist IL-6 was concomitantly administered, the rate of apoptosis in AML cells was significantly reduced. The results suggest that CSE1L may act on AML cells through the JAK2/STAT3 signaling pathway.

In summary, CSE1L knockdown induces apoptosis in AML cells, decreases cell activity and increases the sensitivity of this cell to cytarabine. We suggest that the development of novel CSE1L inhibitors and their combination with the standard chemotherapeutic agent, cytarabine, could be a new therapeutic strategy for the treatment of AML cases with high CSE1L expression. This could be an important discovery in AML drug resistance and provide a new clinical breakthrough to overcome AML drug resistance. In future studies, we will further validate the results by animal experiments.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xiaoyu Liu and Lin Yang are contributed to the work equllly and should be regarded as co-first authors.

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