Open Access

Tetramethylpyrazine inhibits prostate cancer progression by downregulation of forkhead box M1

  • Authors:
    • Yi Zhou
    • Zhigang Ji
    • Weigang Yan
    • Zhien Zhou
    • Hanzhong Li
    • Yu Xiao
  • View Affiliations

  • Published online on: June 29, 2017     https://doi.org/10.3892/or.2017.5768
  • Pages: 837-842
  • Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Tetramethylpyrazine (TMP) has exhibited various anticancer effects. However, its ability to inhibit proliferation, migration, and invasion of prostate cancer (PCa) PC-3 cells is still unclear. In the present study, different concentrations of TMP were co-incubated with PC-3 cells. The pcDNA-FOXM1 plasmid was transfected into cells before treatment with 500 µg/l TMP. The proliferative, migratory and invasive abilities of PC-3 cells were tested by MTT assay, wound healing assay and colony formation assay. Western blotting was used to investigate the expression of FOXM1. We found that, compared with the control, the proliferative, migratory and invasive abilities of PC-3 cells were decreased after incubation with different concentrations of TMP (P<0.01). The expression of FOXM1 was decreased in TMP-treated PC-3 cells (P<0.01). In addition, overexpression of FOXM1 reversed TMP-mediated inhibition of proliferation, migration and invasion of PC-3 cells. We also found that TMP inhibited PCa growth in vivo in a dose-dependent manner. These results suggest that TMP inhibits PC-3 cell proliferation, migration and invasion by downregulation of FOXM1.

Introduction

Prostate cancer (PCa), one of the most prevalent malignancies, is a major cause of cancer-related deaths in men. With the improvement in PSA screening, prostate biopsies, and MRI imaging, prostate tumors are being detected and localized more accurately (1). In addition, the survival rate of PCa patients has greatly increased due to the development of therapeutic strategies including surgery, radiotherapy and pharmacotherapy. However, 5% of PCa patients still suffer from metastatic lesions at the time of diagnosis (2). Therefore, new treatment choices are critically required.

Tetramethylpyrazine (TMP) (2,3,5,6-tetramethylpyrazine; C8H12N2) is one of the bioactive ingredients extracted from Chuanxiong (Ligusticum), a Chinese herb (3). As a Chinese traditional medicine, TMP has been commonly used for the treatment of cardiovascular and neurovascular disorders such as atherosclerosis, angina pectoris and acute ischemic stroke. Recently, it has been shown to exhibit various anticancer effects. Following the report by Fu et al (4) that TMP could inhibit glioma cell activity and glutamate neuro-excitotoxicity, many studies further confirmed the anticancer effect of TMP on lung, breast, ovarian carcinoma, gastric cancer, osteosarcoma and hepatocellular carcinoma (510). However, the ability of TMP to inhibit the progression of prostate cancer and its possible mechanism is still unclear.

The forkhead box M1 (FOXM1) gene is one of the FOX family, which has been shown to play critical roles in the cell fate. In tumorigenesis, many studies have shown that the expression of FOXM1 was increased in multiple human cancers such as hepatocellular carcinoma, breast, esophageal, colorectal and prostate cancer (1114). In addition, the overexpression of FOXM1 was closely correlated with tumor metastasis and progression (13) and its downregulation could inhibit tumor progression. Various studies found that many Chinese traditional medicine inhibited tumor progression by downregulatoin of FOXM1. For example, Yu et al (15) demonstrated that tanshinone IIA suppressed gastric cancer cell migration by inhibition of FOXM1 and Liu et al (16) showed that casticin induced breast cancer cell apoptosis by inhibiting the expression of FOXM1. However, whether TMP could reduce the expression of FOXM1 and the role of FOXM1 in TMP induced inhibition of tumor metastasis has not been reported.

In the present study we first show that TMP inhibited the proliferation, migration, and invasion of prostate cancer in vitro and in vivo. We further demonstrate that downregulation of FOXM1 is the key mechanism by which TMP inhibits prostate cancer progression.

Materials and methods

Cell culture and transfection

Human PCa cell line (PC-3) was obtained from the American Type Culture Collection (ATCC; Manassas, VA, USA) and cultured in RPMI 1640 medium with 10% fetal bovine serum (FBS), 1% 100 mg/ml streptomycin sulfate and 1% 100 U/ml penicillin. The cells were incubated in humidified incubators with 5% CO2 at 37°C.

Human FOXM1 gene was inserted in pcDNA3.1+HA vector by Life Technologies (Shanghai Genechem, Co., Ltd., Shanghai, China) and the empty vector was used as the negative control. After the cells reached 70–80% confluence, pcDNA3.1+HA-FOXM1 and pcDNA3.1+HA empty vector were transfected into the cells with Lipofectamine 2000 according to the manufacturers information.

MTT assay

The proliferative ability of PC-3 cells was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT; Sigma-Aldrich, St. Louis, MO, USA) assay. Approximately 104 cells were seeded into each well of the 96-well plates. PC-3 cells were then transfected with pcDNA3.1+HA-FOXM1 or pcDNA3.1+HA empty vector according to the manufacturers instructions. Six hours after the transfection, the cells were treated with different concentrations of TMP or placebo. After 24, 48 or 72 h of incubation, 25 µl of MTT (5 mg/ml) was added to each well and plates were incubated for 4 h at 37°C. The precipitates in each well were solubilized with 150 µl of dimethyl sulfoxide (DMSO; Sigma-Aldrich) and the plates were read on a microplate reader (Anthos Labtec Instruments GmbH, Salzburg, Austria) at 490 nm. Values were normalized using the control value.

Colony formation assay

For the colony formation assay, PC-3 cells were transfected with pcDNA3.1+HA-FOXM1 or pcDNA3.1+HA empty vector following the manufacturers information. Six hours after the transfection, the cells were treated with different concentrations of TMP or placebo. After culturing them for 14 days, the cells were stained with methylene blue and photographed.

Cell migration assay

The migratory ability of PC-3 cells was measured by wound healing assay. Approximately 106 cells were seeded into each well of the 6-well plates. PC-3 cells were then transfected with pcDNA3.1+HA-FOXM1 or pcDNA3.1+HA empty vector following the manufacturers information. When the transfected cells reached ~90% confluency, the cell scratch spatula was used to create a wound in the cell layer. After washing them with warm phosphate-buffered saline (PBS) thrice, the cells were treated with different concentrations of TMP or placebo. The cells were then incubated at 37°C for 18 h. Digital camera system (Olympus Corp., Tokyo, Japan) was used to acquire images of the scratches of cells after incubating for 0 and 24 h.

Cell invasion assay

The migratory ability of PC-3 cells was measured by Transwell assay. After being synchronized in serum-free medium, PC-3 cells were transfected with pcDNA3.1+HA-FOXM1 or pcDNA3.1+HA empty vector following the manufacturers information. The cells were then plated onto the 24-well upper chamber with a membrane pre-treated with Matrigel (100 µg/well). In the lower portion of the chamber, fresh medium contained 10% FBS was added. After being treated with different concentrations of TMP or placebo for 24 h, the cells on the upper side of the wells were softly scraped off. Cells that migrated to the lower side of the wells were fixed with 4% paraformaldehyde and stained with 0.5% crystal violet. Then, cells from nine independent, randomly chosen visual fields were counted under an immunofluorescence microscope (×200 magnification) for quantification of cells.

Western blotting

Cells and tumor tissues were extracted with RIPA lysis buffer. Protein lysates were then separated by 10% SDS-PAGE and transferred to PVDF. After blocking with blocking buffer for 1 h at room temperature, the membranes were then incubated with the primary antibodies: FOXM1 (1:1,000) and β-actin (1:1,000) overnight at 4°C. The membranes were washed with PSBT twice and then were incubated in HRP-linked secondary antibodies for 2 h. ECL Plus kit was used to detect the western blotting signals. Each blot was repeated three times independently.

In vivo tumor growth assay

All animal procedures and experiments were performed in conformity with the National Institutes of Health Guide for Care and Use of Laboratory Animals. Six-week-old nude mice [BALB/cA-nu (nu/nu)] were procured from Nanjing Animal, Co., Ltd. (Nanjing, China). Normal human prostate cancer cells or PC-3 cells (5×106) consistently expressing FOXM1 were injected subcutaneously in both flanks of the nude mice. All animals developed palpable tumors. The mice were divided into five groups (n=8): group I mice were injected with normal PC-3 cells; group II mice were injected with normal PC-3 cells and treated with 10 mg/kg TMP; group III mice were injected with normal PC-3 cells and treated with 50 mg/kg TMP; group IV mice were injected with normal PC-3 cells and treated with 100 mg/kg TMP; group V mice were injected with PC-3 cells consistently expressing FOXM1 and treated with 50 mg/kg TMP. Treatment was initiated one week after the injection of PC-3 cells. Different concentrations of TMP were administered orally (200 µl/day) as a suspension in 1.5% carboxymethylcellulose on a daily basis for 6 weeks. The control group received 200 µl vehicle without TMP. The mice were observed every 2 days to check for palpable tumor formation. Six weeks after the implantation, xenografts were removed from the mice and weighed. Tumor volume was calculated with the following formula: 4π/3 × (width/2)2 × (length/2).

Statistical analysis

All values were expressed as mean ± SD. All data were analyzed by the SPSS 20.0. Differences among groups were analyzed for statistical significance by using the Students t-test or one-way analysis of variance (ANOVA) followed by Tukeys studentized range (HSD) post-hoc test for multiple comparisons. All experiments were repeated three times. Statistical probability of P<0.05 was considered to be significant.

Results

TMP inhibits PC-3 cell proliferation

Fig. 1 shows the chemical structure of TMP. To test the effect of TMP on PC-3 cell proliferation, MTT assay and colony formation assay were performed. As shown in Fig. 2A, TMP inhibited the proliferation of PC-3 cells in a dose-dependent manner (P<0.05). We also found that TMP suppresses colony formation of PC-3 cells in a dose-dependent manner (Fig. 2B; P<0.05). These results indicated that TMP inhibited PC-3 cell proliferation.

TMP suppressed PC-3 cell migration and invasion

To check the effect of TMP on PC-3 cell migration and invasion, cells were incubated with increasing concentrations of TMP. Images of the scratches were captured 0 and 24 h after addition of TMP. We found that TMP markedly inhibited PC-3 cell migration after 24 h (Fig. 3A; P<0.01). Results of Transwell assay also showed that TMP suppressed the invasive ability of PC-3 cells (Fig. 3B).

TMP decreases the expression of FOXM1 in PC-3 cells

After PC-3 cells were incubated with increasing concentrations of TMP for 48 h, western blot analysis showed that the expression of FOXM1 was decreased by TMP in a dose-dependent manner (Fig. 4; P<0.01).

Overexpression of FOXM1 reverses the effect of TMP on PC-3 cells

To further verify the role of FOXM1 in TMP-induced inhibition of PC-3 proliferation, migration and invasion, pcDNA3.1+HA-FOXM1 were transfected into PC-3 cells to increase the expression of FOXM1. Western blot analysis demonstrated that the FOXM1 protein levels were increased in the cells transfected with pcDNA3.1+HA-FOXM1 compared with the empty vector (Fig. 5; P<0.01).

After being transfected by pcDNA3.1+HA-FOXM1 or empty plasmid, PC-3 cells were incubated with TMP (100 µg/l) or vehicle. Compared with the TMP group, overexpression of FOXM1 increased the proliferative ability of PC-3 cells (Fig. 6A; P<0.01). In addition, we found that compared to the TMP group, overexpression of FOXM1 could also suppress the migratory and invasive ability of PC-3 cells (Fig. 6B and C; P<0.01). These results demonstrated that overexpression of FOXM1 reversed the TMP-induced inhibition of PC-3 cell proliferation, migration and invasion.

TMP suppresses the growth of prostate cancer cells by downregulation of FOXM1 in vivo

To explore the effect of TMP on inhibition of cell proliferation and migration in PC-3 cells, we further measured the effect of TMP on tumor growth in vivo. Treatment with TMP caused a significant decrease in the tumor volume and tumor weight of subcutaneous xenograft tumors in nude mice when compared with the control (Fig. 7A and B; Table I). In addition, the expression level of FOXM1 also declined with TMP treatment (Fig. 7C). We also found that overexpression of FOXM1 reversed the inhibitory effect of TMP on tumor growth (Fig. 8 and Table II). In conclusion, these results indicated that TMP suppressed the growth of prostate cancer cells by downregulation of FOXM1 in vivo.

Table I.

Weight of xenografts in nude mice at different times (mean ± SD).

Table I.

Weight of xenografts in nude mice at different times (mean ± SD).

2 weeks (g)4 weeks (g)6 weeks (g)
Control0.67±0.081.94±0.134.72±0.46
TMP (10 mg/kg)0.62±0.12 1.60±0.16a 2.51±0.31a
TMP (50 mg/kg)0.61±0.09 1.52±0.21a 2.17±0.39a
TMP (100 mg/kg) 0.54±0.07a 1.37±0.19a 1.92±0.12a

a P<0.05 compared with control.

Table II.

Weight of xenografts in nude mice at different times (mean ± SD).

Table II.

Weight of xenografts in nude mice at different times (mean ± SD).

2 weeks (g)4 weeks (g)6 weeks (g)
Control0.67±0.081.94±0.134.72±0.46
TMP0.61±0.09 1.52±0.21a 2.17±0.39a
TMP + FOXM10.64±0.07 1.87±0.19b 4.92±0.12b

a P<0.05 compared with control.

b P<0.05 compared with TMP.

Discussion

Abnormal proliferation and migration of tumor cells are crucial pathological processes involved in malignant tumor progression (1720). Tumor progression is a complex process which includes tumor cell proliferation, migratory tumor cells leaving the primary position and eventually colonizing at distant organs (21). Therefore, it is important to find an effective means to inhibit the proliferation, migration and invasion of cells to improve the prognosis of patients with prostate cancer.

Tetramethylpyrazine (TMP) is one of the active compounds extracted from the Chinese medicinal plant Ligusticum chuanxiong. It has been widely used as an active ingredient in the clinical treatment of neurovascular and cardiovascular diseases. The underlying mechanism may involve inhibition of platelet aggregation, suppression of apoptosis, and scavenging of peroxyl, superoxide and hydroxyl radicals. A substantial amount of evidence has revealed that TMP has antioxidant and antitumor activity. Wang et al (22) reported that TMP inhibited the proliferation of acute lymphocytic leukemia cell lines via downregulation of GSK-3β. Besides, Jia et al (23) found that TMP suppressed lung cancer growth through disrupting angiogenesis via BMP/Smad/Id-1 signaling. In addition, Wang et al (24) demonstrated that TMP exerted antitumor activity in breast cancer cells by targeting mitochondrial complex II. Consistently with these studies, the present study found that TMP inhibited the proliferative, migratory, and invasive ability of PC-3 cells in a dose-dependent manner both in vitro and in vivo. As a multi-target drug, the molecular targets of TMP include apoptosis regulating proteins, transcription factors, growth factors, ion channels and inflammatory mediators (3,24,25). In this study, we found that TMP decreased the expression of FOXM1 in PC-3 cells in a dose-dependent manner.

FOXM1 is an important transcription factor required for tissue development and differentiation in vertebrates (26). FOXM1 binds to sequence-specific motifs on DNA (C/TAAACA) through its DNA-binding domain (DBD) and activates proliferation, migration and EMT associated genes. Aberrant overexpression of FOXM1 is a key feature in oncogenesis and progression of many human cancers (27). Recently, overexpression of FOXM1 and its correlation with poor prognosis in patients with malignant tumors has been reported in many cancers including gastric cancer (2832). Zhang et al (33) reported that downregulation of FOXM1 could suppress PLK1-regulated cell cycle progression in renal cancer cells. Additionally, Inoguchi et al (34) found that microRNA-24-1 inhibited bladder cancer cell proliferation through targeting FOXM1. In our results, we found that TMP decreased the expression of FOXM1 in PC-3 cells in a dose-dependent manner. Therefore, we hypothesized that TMP inhibited PC-3 cell proliferation and migration by downregulation of FOXM1. In addition, our results showed that overexpression of FOXM1 promoted the proliferative, migratory, and invasive ability of PC-3 cells and reversed the tumor inhibitory effect of TMP on PCa both in vitro and in vivo. These results strongly indicate that TMP inhibited PC-3 cell proliferation, migration, and invasion by downregulation of FOXM1.

In summary, the present study provides new insights into the effect of TMP on PC-3 cells and its related mechanism. This study suggests that TMP inhibits proliferation, migration, and invasion of PC-3 cells at least partly through downregulation of FOXM1.

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Zhou Y, Ji Z, Yan W, Zhou Z, Li H and Xiao Y: Tetramethylpyrazine inhibits prostate cancer progression by downregulation of forkhead box M1. Oncol Rep 38: 837-842, 2017
APA
Zhou, Y., Ji, Z., Yan, W., Zhou, Z., Li, H., & Xiao, Y. (2017). Tetramethylpyrazine inhibits prostate cancer progression by downregulation of forkhead box M1. Oncology Reports, 38, 837-842. https://doi.org/10.3892/or.2017.5768
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Zhou, Y., Ji, Z., Yan, W., Zhou, Z., Li, H., Xiao, Y."Tetramethylpyrazine inhibits prostate cancer progression by downregulation of forkhead box M1". Oncology Reports 38.2 (2017): 837-842.
Chicago
Zhou, Y., Ji, Z., Yan, W., Zhou, Z., Li, H., Xiao, Y."Tetramethylpyrazine inhibits prostate cancer progression by downregulation of forkhead box M1". Oncology Reports 38, no. 2 (2017): 837-842. https://doi.org/10.3892/or.2017.5768