Matrine inhibits the metastatic properties of human cervical cancer cells via downregulating the p38 signaling pathway

  • Authors:
    • Xiaoling Wu
    • Jie Zhou
    • Dongge Cai
    • Mu Li
  • View Affiliations

  • Published online on: July 3, 2017     https://doi.org/10.3892/or.2017.5787
  • Pages: 1312-1320
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Matrine is a traditional Chinese herbal medicine that shows antitumor efficacy for many types of cancer. The present study evaluated the antitumor efficacy of matrine on cervical cancer and to investigate the underlying mechanisms. We performed MTT assays, and in vitro invasion and migration assays, and P1 L6 found that matrine significantly inhibited cervical cancer cell growth by inducing apoptosis, and suppressed the invasion and migration ability of cervical cancer cells in vitro in a concentration-dependent manner. Mechanistically, we found that matrine decreased the expression and activity of the extracellular matrix factors, matrix metalloproteinases-2 (MMP-2) and MMP-9 via the suppression of p38 signaling pathway. In addition, when cervical cancer cells were grown as xenografts in nude mice, intraperitoneal (i.p.) injection of matrine induced a significant dose-dependent decrease in tumor growth. Taken together, these findings suggest that a potential mechanism by which matrine inhibits the growth and metastasis of cervical cancer through downregulating the p38 signaling pathway.

Introduction

Cervical cancer is the fourth most common cause of cancer-related mortality in women worldwide (1). In the clinical, surgery may be used alone or with radiation therapy and chemotherapy for cervical cancer treatment, depending on the stage of the cancer and the patients preferences. However, metastasis and recurrence of invasive cervical cancer will lead to poor prognosis and treatment failure. Therefore, it is urgent to develop alternative treatment options which are more effective and less toxic. In recent years, considerable attention has been given to the application of traditional Chinese medicine (TCM) in anticancer therapy (24). Matrine, which was approved by Chinese FDA (CFDA) in 1995, is derived primarily from Sophora species plants and has a chemical formula of C15H24N2O (5). Matrine exhibits a wide range of pharmacological effects and has long been applied to treat viral hepatitis (6), neuropathic pain (7), isoproterenol-induced cardiotoxicity inflammatory and other diseases (8,9). In addition, increasing evidence has revealed that matrine displays anticancer effects in various cancers, such as gastric (10), rhabdomyosarcoma (11), acute myeloid leukemia (12), osteosarcoma (13), prostate (14), breast (15) and lung cancer (16). Moreover, the antitumor mechanisms of matrine have been demonstrated to involve the blockade of cell cycle progression, the induction of apoptosis, the regulation of oncogene expression, the inhibition of cytokine production and the modulation of signaling pathways (1719).

Metastasis is a multi-step process that involves various cytophysiological changes, among which the degradation of the extracellular matrix (ECM) is very important (20). Matrix metalloproteinases-2 (MMP-2) and MMP-9 play important roles in degrading basement membranes and are intricately involved in cancer invasion and metastasis (2123). The mitogen-activated protein kinases (MAPKs) are important components of intracellular signaling networks that regulate cell proliferation, differentiation, cellular stress responses, apoptosis and tumor progression (24,25). The activation of p38 signaling pathway, which belongs to MAPKs, is correlated to the development of cancer (2628). Tumor cells need to modulate p38 activity to successfully metastasize (29). Recent studies showed that p38 signaling pathway participates in the invasion and metastasis of cervical cancer (3032). Notably, Zhang et al (33) reported that matrine inhibited HeLa cell adhesion and migration through the inhibition of the activity of cAMP-dependent protein kinase (PKA) and vasodilator-stimulated phosphoprotein (VASP). On the other hand, Tan et al (34) recently reported that matrine activated the p38 pathway and promoted caspase-dependent apoptosis by inducing the generation of ROS in non-small cell lung cancer cells. Therefore, in the present study we aimed to investigate the effects of matrine against the invasion and metastasis of cervical cancer and explore whether the mechanism of its actions is associated with the p38 signaling pathway.

Materials and methods

Reagents

Matrine, dimethyl sulfoxide dissolving (DMSO), SB203580 and anisomycin were purchased from Sigma-Aldrich (St. Louis, MO, USA). Dulbecco's modified Eagle's medium (DMEM), fetal bovine serum (FBS), penicillin and streptomycin were purchased from Invitrogen (Carlsbad, CA, USA). Anti-p38, anti-phospho-p38 (p-p38), anti-MMP-2, anti-MMP-9, anti-Akt, anti-pAkt, anti-NF-κB p65 and anti-p-p65, antibodies were purchased from Cell Signaling Technology (Danvers, MA, USA). Anti-β-actin antibody was purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA).

Cell culture

Human cervical cancer cell lines HeLa and C33A were purchased from the American Type Culture Collection (ATCC; Manassas, VA, USA) and were cultured in DMEM supplemented with 10% FBS, 100 U/ml penicillin and 100 µg/ml streptomycin. All cells were incubated at 37°C with 5% CO2.

Cell viability assay

Cell survival was assessed using standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay kit (Sigma-Aldrich) according to the manufacturers instructions. Briefly, cells were seeded in 96-well culture plate (Corning Costar, Corning, NY, USA) at 2×104 cells/well in quadruplicate. The cells were treated with different concentrations of matrine (0–400 µg/ml) for 24, 48 or 72 h, then cells were washed twice with phosphate-buffered saline (PBS) and incubated with 20 µl MTT (5 mg/ml) for 4 h at 37°C. The solution was then discarded and 150 µl DMSO were added to each well. The optical density was measured in a microplate reader at 562 nm. Each experiment was performed in triplicate.

Flow cytometric analysis of apoptosis

Apoptosis was analyzed in vitro using a fluorescence-activated cell sorter (FACS) Annexin V assay kit (BD Biosciences, San Jose, CA, USA) according to the manufacturers instructions. Briefly, the cells were exposed to oxymatrine at concentrations of 0, 25, 50 and 100 µg/ml for 48 h, then harvested and resuspended in binding buffer. Follow staining in duplicate with 5 µl of Annexin V-FITC and 5 µl of propidium iodide (PI) for 30 min in the dark, the samples were analyzed by flow cytometry using a FACSCalibur system (BD Biosciences). The percentage of apoptotic cells is referred as the apoptotic index. Each experiment was performed in triplicate.

In vitro invasion and migration assays

The in vitro invasion and migration activity was measured according to the methods previously described (35). HeLa and C33A cervical cells were pretreated with 0, 25, 50 and 100 µg/ml matrine or SB203580 (10 µM) or anisomycin (5 µM/l) for 24 h, surviving cells were harvested and seeded to Boyden chamber (Neuro Probe, Inc., Cabin John, MD, USA) at 105 cells/well in serum-free medium and then incubated for 24 h at 37°C. At the end point, the cells on the upper side of inserts were completely removed by swabbing, while the cells on the bottom side of the filter were fixed, stained and counted. For invasion assay, 50 µl Matrigel (25 µg/ml; BD Biosciences, Bedford, MA, USA) was applied to 8-mm pore size polycarbonate membrane filters.

Quantitative real-time RT-PCR (qRT-PCR)

Total RNAs were prepared using the RNeasy Mini kit (Invitrogen). cDNA was synthesized with SuperScript II Reverse Transcriptase (Invitrogen). qRT-PCR was performed using an iQ5 Real-Time PCR Detection System (Bio-Rad Laboratories, Richmond, CA, USA) with SYBR Premix Ex Taq™ II (Takara Bio, Tokyo, Japan) according to the manufacturers instructions. Gene-specific primers were as follows: β-actin: forward, CCATCG TCCACCGCAAAT and reverse, CATGCCAATCTCATCT TGTTT; MMP-2: forward, CTCATCGCAGATGCCTGGAA and reverse, TTCAGGTAATAGGCACCCTTGAAGA; MMP-9: forward, GTCCACCCTTGTGCTCTTCC and reverse, GCCACCCGAGTGTAACCAT. The analysis of the relative gene copy number data for MMP-2 and MMP-9 was performed using the comparative ∆∆CT method and were normalized by the endogenous β-actin in each sample. All experiments had at least biological duplicates and assay triplicates.

Gelatin zymography

The cells were treated with different concentrations of matrine at 37°C for 24 h and samples of conditioned media were collected. Briefly, the conditioned medium was adjusted to the same quantity of total protein, and then treated with sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) non-reducing sample buffer without boiling. Samples were separated by 0.1% gelatin-8% SDS-PAGE electrophoresis. Afterwards, the gels were soaked twice in 2.5% Triton X-100 for 30 min at room temperature (RT), and incubated in reaction buffer (10 mM CaCl2, 40 mM Tris-HCl and 0.01% NaN3, pH 8.0) at 37°C for 12 h. Gels were rinsed with distilled water, stained with Coomassie brilliant blue R-250 staining solution (Bio-Rad Laboratories). The gelatinolytic activities were densitometrically quantified and analyzed by an image analysis system (Bio-Rad Laboratories).

Western blot analysis

Cells were suspended in lysis buffer (40 mmol/l Tris-HCl, 1 mmol/l EDTA, 150 mmol/l KCl, 100 mmol/l NaVO3, 1% Triton X-100, 1 mmol/l PMSF, pH 7.5) and the lysates were collected. Equal amounts of proteins were separated by 10% SDS-PAGE gel electrophoresis and transferred onto polyvinylidene fluoride (PVDF) membranes (Milipore, Billerica, MA, USA). The membranes were subsequently blocked in defatted milk (Heilongjiang Wondersun, Harbin, China) (5% in Tris-buffered saline with Tween-20 buffer) at RT for 1 h to block non-specific binding and then incubated overnight at 4°C with antibodies against p38, p-P38, MMP-2, MMP-9, Akt, p-Akt, p65, p-p65 or β-actin. The membranes were then incubated with an HRP goat anti-mouse or anti-rabbit IgG antibody for 1 h at RT. The bands were detected with an enhanced chemiluminescence kit (Amersham ECL Plus; GE Healthcare, Freiburg, Germany) and exposed by autoradiography. The densitometric analysis was performed using ImageJ software (NIH Image, Bethesda, MD, USA) and the results were expressed as arbitrary units (a.u.).

Animal and tumor xenograft assays

To assess in vivo tumorigenicity, 4-to-6-weeks-old BALB/c athymic nude mice were purchased from the Experimental Animal Center of Xi'an Jiaotong University Medical College (Xi'an, China). Suspensions of HeLa tumor cells (1×106 viable cells/mouse) were implanted into the right flank region of BALB/c nude mice. At 48 h after the injection (day 1), the mice were randomly divided into two groups (n=6). The animals were pair-matched so that the median tumor volume for each group was similar: the treatment group received matrine at 50 mg/kg per day via intragastric administration; the control group received an equal volume of normal saline. The tumor volumes were measured twice weekly with calipers and calculated according to the standard formula: (length × width2)/2. After 3 weeks of drug administration, the mice were sacrificed and the tumors were dissected and weighed. The experimental protocols were approved by the Animal Care and Use Committee of the Medical School of Xi'an Jiaotong University.

Statistical analysis

Statistical analyses were performed using the GraphPad Prism 5.01 software (GraphPad Software, Inc., La Jolla, CA, USA). All data are expressed as mean ± standard deviation (SD). The Student's t-test was used for comparisons between two groups and one-way or two-way analysis of variance (ANOVA) test was used to analyze the statistical differences between the groups under different conditions. Correlation analysis was performed by the Z-test. P<0.05 was regarded as statistically significant. All statistical tests and corresponding P-values were two-sided.

Results

Matrine inhibits the proliferation of human cervical cancer cells by inducing apoptosis

The inhibitory effects of matrine at various concentrations (0–400 µg/ml) on the growth of HeLa and C33A cervical cancer cells were assessed by MTT assay. As shown in Fig. 1A and B, at the concentration of 50–100 µg/ml of matrine, HeLa and C33A cells showed a sharp decrease in cell viability (P<0.05), and the growth inhibition rates were increased with elevated matrine concentration (>100 µg/ml) (P<0.01), suggesting that matrine inhibits the growth of cervical cancer cells in a dose-dependent manner in vitro. In addition, during the prolonged treatments (48 and 72 h), matrine showed a significantly greater inhibitory effect than that at 24 h (P<0.01).

It has been reported that matrine exhibits antitumor effects by inducing apoptosis of various cancer cells (36,37). Thus, to examine the effects of matrine on cervical cancer cell apoptosis, matrine-treated cells were stained with Annexin V/PI and subjected to flow cytometric analysis. As shown in Fig. 1C, matrine induced a significant increase in the proportion of apoptotic HeLa and C33A cells, matrine at concentration of 25, 50 and 100 µg/ml caused 8.91±2.11, 19.53±7.17 and 38.41±8.13% of HeLa cells and 5.31±2.29, 15.37±3.01 and 28.91±5.63% of C33A cells to undergo apoptosis, respectively. Based on previous in vitro studies (33), we selected concentrations of 25, 50 and 100 µg/ml matrine for subsequent investigation to rule out the cytotoxicity. Taken together, these results suggest that matrine significantly inhibits the growth of cervical cancer cells at a dose- and time-dependent manner by inducing apoptosis.

Matrine inhibits the migration and invasion of cervical cancer cells

Abnormal growth and metastasis of cancer cells are regarded as the important biological characteristics of cancers. Next, we examined the effects of matrine on the migration and invasion of cervical cancer cells. Matrine at the concentrations of 25, 50 and 100 µg/ml significantly reduced the rate of HeLa cells migration compared with the control group (Fig. 2A). Matrine at concentrations of 25, 50 and 100 µg/ml caused 40.53±2.05, 49.85±7.48 74.29±4.26% inhibition of cell migration, respectively (Fig. 2C). In addition, the invasion assay revealed similar results (Fig. 2B and D), the inhibition of HeLa cell invasion was 40.1±1.95, 78.84±3.05 and 92.74±3.75%, at concentrations of 25, 50 and 100 µg/ml, respectively. Similar inhibitory effects of matrine on cell migration and invasion were observed in C33A cells (Fig. 2). These findings suggest that matrine inhibits the migration and invasion of cervical cancer cells in a concentration-dependent manner.

Matrine suppresses the expression and activity of MMP-2 and MMP-9

The complex dynamics of tumor invasion and metastasis often involves the destruction of extracellular matrix (ECM) by enzymes such as serine proteases, threonine proteases and matrix metalloproteinases (MMPs) (38). To further explore the potential mechanism by which matrine inhibits cervical cancer invasion and metastasis, we examined the expression and activity of MMP-2 and MMP-9 in HeLa cells exposed to different concentrations of matrine. Western blot analysis showed that matrine significantly reduced the protein levels of MMP-2 and MMP-9 in a concentration-dependent manner (Fig. 3A and B). Gelatin zymography showed that the activities of MMP-2 and MMP-9 were significantly inhibited by matrine in a concentration-dependent manner (Fig. 3C). MMP-2 activity was reduced to 79.98±8.73, 37.5±4.67 and 22.08±1.67%, and MMP-9 activity was reduced to 70.24±7.87, 23.68±4.25 and 21.60±1.39%, in cells treated with 25, 50 and 100 µg/ml of matrine, respectively (Fig. 3D). Collectively, these data suggest that matrine significantly inhibits the expression and activity of MMP-2 and MMP-9.

Matrine inhibits the p38 signaling pathway in cervical cancer cells

Activation of p38 is required for the invasion of human cervical cancer cells (39). Thus, we wondered whether the anti-metastatic effect of matrine is related to the modulation of p38 signaling pathway in cervical cancer cells. Western blot analysis showed that the level of phosphorylated (activated) p38 in HeLa cells was downregulated upon matrine treatment in a concentration-dependent manner (Fig. 4B and C). To confirm that the inhibitory effects of matrine on cell invasion and MMP-2 and MMP-9 expression was associated with the downregulated p38 signaling pathway, HeLa cells were pretreated with a p38 inhibitor (SB203580, 10 µM) for 30 min and then incubated in the presence or absence of matrine (50 µg/ml) for 24 h. The results showed that treatment with SB203580 and matrine significantly reduced both cell invasion (Fig. 4D and F) and the levels of MMP-2, MMP-9 and p-P38 (Fig. 4E and G). Furthermore, anisomycin, a p38 activator, blocked the effects of matrine (Fig. 5). Taken together, these results reveal that the inhibition of cervical cancer cell invasion and MMP-2 and MMP-9 expression by matrine is mediated by the suppression of the p38 signaling pathway.

In vivo inhibition of cervical cancer tumor growth by matrine

To evaluate the effects of matrine on tumor growth in vivo, we performed nude mouse xenograft assay of HeLa cells as previously described (40). The time courses of HeLa xenograft growth with and without matrine treatment are shown in Fig. 6A. The average volume of xenograft treated with matrine at 21 days after cell implantation was significantly less than that of control group. At the end of the experiment, the xenograft tumors were dissected and weighed. Matrine significantly decreased the solid tumor mass and the inhibitory rate of tumor weight was 58.33% (Fig. 6B). Moreover, we assessed the levels of MMP-2, MMP-9, p38, p-p38, Akt, p-Akt, p65 and p-p65 in the tumors dissected from nude mice. Western blot analysis showed that matrine treatment led to significantly reduced levels of MMP-2, MMP-9 and p-p38, but had weaker effects on the levels of p-Akt and p-p65 (Fig. 6C). Taken together, these findings suggest that matrine inhibits cervical cancer growth through specific suppression of p38 signaling.

Discussion

In the present study, we confirmed that matrine significantly inhibited the growth of human cervical cancer HeLa and C33A cells in vitro in a dose- and time-dependent manner by inducing apoptosis. In addition, we demonstrated that matrine significantly inhibited the invasive and metastatic ability of cervical cancer cells in vitro by the downregulation of MMPs through inhibiting the p38 signaling pathway.

Recently, natural products have opened up a new avenue for successful cancer treatment because of their pharmacological activity and therapeutic possibilities (41,42). Matrine has been shown as a new antitumor natural product (43). However, the anticancer efficacy of matrine and the underlying mechanisms in cervical cancer are not clear. To explore the role of matrine in cervical cancer, we first performed MTT assay and found that matrine significantly inhibited cervical cancer cell growth in a dose- and time-dependent manner. To rule out the cytotoxicity of matrine, we chose concentrations of 0, 25, 50 and 100 µg/ml matrine for subsequent experiments.

A failure of cancer cells to undergo apoptosis is a common feature of many cancers. Thus, many anticancer drugs activate apoptotic pathways to eliminate cells that harbor genetic damage or divide inappropriately, which is a predominant antitumor mechanism (36). It has been reported that matrine exerts its antitumor effects by inhibiting the proliferation and inducing the apoptosis of gastric cancer cells as well as leukemic and glioma cells (10,17,44). Consistent with these previous studies, we confirmed that matrine induced cervical cancer cell apoptosis in a dose-dependent manner in the range of 25–100 µg/ml. Taken together, these data indicate that matrine inhibits the growth of human cervical cancer cells by inducing apoptosis.

Metastasis is one of the leading causes of cancer-related death among cervical cancer patients. To further examine the effects of matrine on cervical cancer cell migration and invasion, we performed cell migration and invasion assay. The results showed that matrine could significantly inhibit the migration and invasion of cervical cancer cells at non-toxic doses (no more than 100 µg/ml). Zhang et al (33) demonstrated that matrine could suppress HeLa cell adhesion and migration, and this was correlated to decreased VASP phosphorylation. However, the development of metastasis is a complex series of steps (45,46). Successful implantation and invasion are closely linked to the degradation of ECM by MMPs. MMPs, especially MMP-2 and MMP-9, play critical roles in the degradation of type IV collagen, a major constituent of the ECM, and are closely related to the invasion and metastasis of various cancer cells (2123). Consistent with previous studies (14,47), we found that matrine suppressed the expression and activity of MMP-2 and MMP-9 in cervical cancer cells. These results indicate that the anti-metastatic effect of matrine on HeLa cells is correlated with the downregulation of MMP-2 and MMP-9.

The expression of proteinases is regulated by multiple signaling cascades, including p38 signaling pathway (27,4850). p38 is relatively inactive in the unphosphorylated form and can be activated rapidly by MAPK kinase-3 and −6 upon exposure to cellular stress or inflammatory cytokines (5153). p38 signaling pathway induces the expression of MMPs and thereby promotes the degradation of ECM proteins, leading to cell invasion (54). p38 has also been reported as a downstream target of matrine in many cells (34,47). Therefore, we hypothesized that the anti-invasion effect of matrine may be associated with the inhibition of p38 signaling pathway. To confirm it, we determined the level of phosphorylated (activated) p38 and demonstrated that the phosphorylation (activation) of p38 was significantly reduced in HeLa cells treated with matrine, compared to control cells. Furthermore, we employed specific p38 inhibitor (SB203580) and activator (anisomycin). We found that treatment with SB203580 significantly reduced cell invasion, accompanied by decreased MMP-2 and MMP-9 protein expression. Anisomycin could partly abolish the inhibition effects of matrine on the invasion of HeLa cells and the expression and activity of MMP-2/−9. These results indicate that matrine inhibits cell invasion and decreases the expression and activity of MMP-2 and MMP-9 via suppressing the activation of p38 signaling pathway in HeLa cells. The mechanisms of action of matrine against cancer cell invasion have been shown to be associated with EGF/VEGF-VEGFR1-Akt-NF-κB signaling (55). We also noted that matrine produced suppressing effect on activity of Akt and p65, even though weaker. Previous studies demonstrated that S100A8/9 promoted gastric cancer cell migration and invasion through p38 MAPK-dependent NF-κB activation (56). Thus, we presumed that there might be a potential link between p38 and Akt-NF-κB in cervical cancer cells treated with matrine. Therefore, it is necessary to further investigate whether pro-inflammatory cytokines or other signaling pathways contribute to the inhibitory effects of matrine on cervical cancer invasion and metastasis.

In conclusion, we demonstrated the inhibitory effects of matrine on the growth, invasion and metastastic capabilities of cervical cancer cells. Mechanistically, we found that matrine decreased the expression and activity of MMP-2 and MMP-9 via the suppression of p38 signaling pathway. Taken together, these findings suggest that matrine inhibits the growth and metastasis of cervical cancer through downregulating the p38 signaling pathway, and provide evidence that matrine has potential application in treating cervical cancer progression and metastasis.

Acknowledgements

We thank Dr Kunlun Chen for excellent technical assistance.

References

1 

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Li Y, Kong D, Wang Z and Sarkar FH: Regulation of microRNAs by natural agents: An emerging field in chemoprevention and chemotherapy research. Pharm Res. 27:1027–1041. 2010. View Article : Google Scholar : PubMed/NCBI

3 

Tseng CY, Lin CH, Wu LY, Wang JS, Chung MC, Chang JF and Chao MW: Potential combinational anti-cancer therapy in non-small cell lung cancer with traditional chinese medicine Sun-Bai-Pi extract and cisplatin. PLoS One. 11:e01554692016. View Article : Google Scholar : PubMed/NCBI

4 

Teng ZY, Cheng XL, Cai XT, Yang Y, Sun XY, Xu JD, Lu WG, Chen J, Hu CP, Zhou Q, et al: Ancient Chinese formula Qiong-Yu-Gao protects against cisplatin-induced nephrotoxicity without reducing anti-tumor activity. Sci Rep. 5:155922015. View Article : Google Scholar : PubMed/NCBI

5 

Lai JP, He XW, Jiang Y and Chen F: Preparative separation and determination of matrine from the Chinese medicinal plant Sophora flavescens Ait by molecularly imprinted solid-phase extraction. Anal Bioanal Chem. 375:264–269. 2003. View Article : Google Scholar : PubMed/NCBI

6 

Zhang YB, Zhan LQ, Li GQ, Wang F, Wang Y, Li YL, Ye WC and Wang GC: Dimeric matrine-type alkaloids from the roots of Sophora flavescens and their anti-hepatitis B virus activities. J Org Chem. 81:6273–6280. 2016. View Article : Google Scholar : PubMed/NCBI

7 

Gong SS, Li YX, Zhang MT, Du J, Ma PS, Yao WX, Zhou R, Niu Y, Sun T and Yu JQ: Neuroprotective effect of matrine in mouse model of vincristine-induced neuropathic pain. Neurochem Res. 41:3147–3159. 2016. View Article : Google Scholar : PubMed/NCBI

8 

Wu G, Zhou W, Zhao J, Pan X, Sun Y, Xu H, Shi P, Geng C, Gao L and Tian X: Matrine alleviates lipopolysaccharide-induced intestinal inflammation and oxidative stress via CCR7 signal. Oncotarget. 8:11621–11628. 2017.PubMed/NCBI

9 

Kan QC, Zhang HJ, Zhang Y, Li X, Xu YM, Thome R, Zhang ML, Liu N, Chu YJ, Zhang GX, et al: Matrine treatment blocks NogoA-induced neural inhibitory signaling pathway in ongoing experimental autoimmune encephalomyelitis. Mol Neurobiol. Dec 9–2016.doi.org/10.1007/s12035-016-0333-1. View Article : Google Scholar

10 

Dai ZJ, Gao J, Ji ZZ, Wang XJ, Ren HT, Liu XX, Wu WY, Kang HF and Guan HT: Matrine induces apoptosis in gastric carcinoma cells via alteration of Fas/FasL and activation of caspase-3. J Ethnopharmacol. 123:91–96. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Li L, Xue T, Xu W and Zhou B: Effect of matrine combined with cisplatin on the expression of XIAP in human rhabdomyosarcoma RD cells. Oncol Lett. 12:3793–3798. 2016.PubMed/NCBI

12 

Wu J, Hu G, Dong Y, Ma R, Yu Z, Jiang S, Han Y, Yu K and Zhang S: Matrine induces Akt/mTOR signalling inhibition-mediated autophagy and apoptosis in acute myeloid leukaemia cells. J Cell Mol Med. 21:1171–1181. 2016. View Article : Google Scholar : PubMed/NCBI

13 

Ma K, Huang MY, Guo YX and Hu GQ: Matrine-induced autophagy counteracts cell apoptosis via the ERK signaling pathway in osteosarcoma cells. Oncol Lett. 12:1854–1860. 2016.PubMed/NCBI

14 

Huang H, Du T, Xu G, Lai Y, Fan X, Chen X, Li W, Yue F, Li Q, Liu L, et al: Matrine suppresses invasion of castration-resistant prostate cancer cells by downregulating MMP-2/9 via NF-kappaB signaling pathway. Int J Oncol. 50:640–648. 2016.PubMed/NCBI

15 

Li LQ, Li XL, Wang L, Du WJ, Guo R, Liang HH, Liu X, Liang DS, Lu YJ, Shan HL, et al: Matrine inhibits breast cancer growth via miR-21/PTEN/Akt pathway in MCF-7 cells. Cell Physiol Biochem. 30:631–641. 2012. View Article : Google Scholar : PubMed/NCBI

16 

Wu L, Wang G, Wei J, Huang N, Zhang S, Yang F, Li M, Zhou G and Wang L: Matrine derivative YF-18 inhibits lung cancer cell proliferation and migration through down-regulating Skp2. Oncotarget. 8:11729–11738. 2017.PubMed/NCBI

17 

Ma L, Zhu Z, Jiang L, Sun X, Lu X, Zhou M, Qian S and Jianyong L: Matrine suppresses cell growth of human chronic myeloid leukemia cells via its inhibition of the interleukin-6/Janus activated kinase/signal transducer and activator of transcription 3 signaling cohort. Leuk Lymphoma. 56:2923–2930. 2015. View Article : Google Scholar : PubMed/NCBI

18 

Huang J and Xu H: Matrine: Bioactivities and structural modifications. Curr Top Med Chem. 16:3365–3378. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Yong J, Wu X and Lu C: Anticancer advances of matrine and its derivatives. Curr Pharm Des. 21:3673–3680. 2015. View Article : Google Scholar : PubMed/NCBI

20 

Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM and Shafie S: Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature. 284:67–68. 1980. View Article : Google Scholar : PubMed/NCBI

21 

Osman B, Akool S, Doller A, Müller R, Pfeilschifter J and Eberhardt W: Differential modulation of the cytokine-induced MMP-9/TIMP-1 protease-antiprotease system by the mTOR inhibitor rapamycin. Biochem Pharmacol. 81:134–143. 2011. View Article : Google Scholar : PubMed/NCBI

22 

Kim JH, Kim JH, Kim SC, Yi YS, Yang WS, Yang Y, Kim HG, Lee JY, Kim KH, Yoo BC, et al: Adenosine dialdehyde suppresses MMP-9-mediated invasion of cancer cells by blocking the Ras/Raf-1/ERK/AP-1 signaling pathway. Biochem Pharmacol. 86:1285–1300. 2013. View Article : Google Scholar : PubMed/NCBI

23 

Chang WL, Yu CC, Chen CS and Guh JH: Tubulin-binding agents down-regulate matrix metalloproteinase-2 and −9 in human hormone-refractory prostate cancer cells - a critical role of Cdk1 in mitotic entry. Biochem Pharmacol. 94:12–21. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Kim EK and Choi EJ: Compromised MAPK signaling in human diseases: An update. Arch Toxicol. 89:867–882. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Yang M and Huang CZ: Mitogen-activated protein kinase signaling pathway and invasion and metastasis of gastric cancer. World J Gastroenterol. 21:11673–11679. 2015. View Article : Google Scholar : PubMed/NCBI

26 

Wang XF, Zhou QM, Lu YY, Zhang H, Huang S and Su SB: Glycyrrhetinic acid potently suppresses breast cancer invasion and metastasis by impairing the p38 MAPK-AP1 signaling axis. Expert Opin Ther Targets. 19:577–587. 2015. View Article : Google Scholar : PubMed/NCBI

27 

Muranen T, Selfors LM, Hwang J, Gallegos LL, Coloff JL, Thoreen CC, Kang SA, Sabatini DM, Mills GB and Brugge JS: ERK and p38 MAPK activities determine sensitivity to PI3K/mTOR inhibition via regulation of MYC and YAP. Cancer Res. 76:7168–7180. 2016. View Article : Google Scholar : PubMed/NCBI

28 

Kamel WA, Sugihara E, Nobusue H, Yamaguchi-Iwai S, Onishi N, Maki K, Fukuchi Y, Matsuo K, Muto A, Saya H, et al: Simvastatin-induced apoptosis in osteosarcoma cells: A key role of RhoA-AMPK/p38 MAPK signaling in antitumor activity. Mol Cancer Ther. 16:182–192. 2017. View Article : Google Scholar : PubMed/NCBI

29 

del Barco Barrantes I and Nebreda AR: Roles of p38 MAPKs in invasion and metastasis. Biochem Soc Trans. 40:79–84. 2012. View Article : Google Scholar : PubMed/NCBI

30 

Kumar V, Behera R, Lohite K, Karnik S and Kundu GC: p38 kinase is crucial for osteopontin-induced furin expression that supports cervical cancer progression. Cancer Res. 70:10381–10391. 2010. View Article : Google Scholar : PubMed/NCBI

31 

Chou RH, Hsieh SC, Yu YL, Huang MH, Huang YC and Hsieh YH: Fisetin inhibits migration and invasion of human cervical cancer cells by down-regulating urokinase plasminogen activator expression through suppressing the p38 MAPK-dependent NF-κB signaling pathway. PLoS One. 8:e719832013. View Article : Google Scholar : PubMed/NCBI

32 

Feng M, Wang Y, Chen K, Bian Z, Jinfang Wu and Gao Q: IL-17A promotes the migration and invasiveness of cervical cancer cells by coordinately activating MMPs expression via the p38/NF-κB signal pathway. PLoS One. 9:e1085022014. View Article : Google Scholar : PubMed/NCBI

33 

Zhang L, Wang T, Wen X, Wei Y, Peng X, Li H and Wei L: Effect of matrine on HeLa cell adhesion and migration. Eur J Pharmacol. 563:69–76. 2007. View Article : Google Scholar : PubMed/NCBI

34 

Tan C, Qian X, Jia R, Wu M and Liang Z: Matrine induction of reactive oxygen species activates p38 leading to caspase-dependent cell apoptosis in non-small cell lung cancer cells. Oncol Rep. 30:2529–2535. 2013.PubMed/NCBI

35 

Yuan X, Yu L, Li J, Xie G, Rong T, Zhang L, Chen J, Meng Q, Irving AT, Wang D, et al: ATF3 suppresses metastasis of bladder cancer by regulating gelsolin-mediated remodeling of the actin cytoskeleton. Cancer Res. 73:3625–3637. 2013. View Article : Google Scholar : PubMed/NCBI

36 

Yang N, Han F, Cui H, Huang J, Wang T, Zhou Y and Zhou J: Matrine suppresses proliferation and induces apoptosis in human cholangiocarcinoma cells through suppression of JAK2/STAT3 signaling. Pharmacol Rep. 67:388–393. 2015. View Article : Google Scholar : PubMed/NCBI

37 

Xu GP, Zhao W, Zhuang JP, Zu JN, Wang DY, Han F, Zhang ZP and Yan JL: Matrine inhibits the growth and induces apoptosis of osteosarcoma cells in vitro by inactivating the Akt pathway. Tumour Biol. 36:1653–1659. 2015. View Article : Google Scholar : PubMed/NCBI

38 

Thakur V and Bedogni B: The membrane tethered matrix metalloproteinase MT1-MMP at the forefront of melanoma cell invasion and metastasis. Pharmacol Res. 111:17–22. 2016. View Article : Google Scholar : PubMed/NCBI

39 

Yan L, Liu X, Yin A, Wei Y, Yang Q and Kong B: Huaier aqueous extract inhibits cervical cancer cell proliferation via JNK/p38 pathway. Int J Oncol. 47:1054–1060. 2015.PubMed/NCBI

40 

Li M, Su BS, Chang LH, Gao Q, Chen KL, An P, Huang C, Yang J and Li ZF: Oxymatrine induces apoptosis in human cervical cancer cells through guanine nucleotide depletion. Anticancer Drugs. 25:161–173. 2014. View Article : Google Scholar : PubMed/NCBI

41 

Gogoi B, Gogoi D, Silla Y, Kakoti BB and Bhau BS: Network pharmacology-based virtual screening of natural products from Clerodendrum species for identification of novel anti-cancer therapeutics. Mol Biosyst. 13:406–416. 2017. View Article : Google Scholar : PubMed/NCBI

42 

Wang X, Xu L, Lao Y, Zhang H and Xu H: Natural products targeting EGFR signaling pathways as potential anticancer drugs. Curr Protein Pept Sci. Jan 5–2017.(Epub ahead of print).

43 

Liu Y, Xu Y, Ji W, Li X, Sun B, Gao Q and Su C: Anti-tumor activities of matrine and oxymatrine: literature review. Tumour Biol. 35:5111–5119. 2014. View Article : Google Scholar : PubMed/NCBI

44 

Zhang S, Qi J, Sun L, Cheng B, Pan S, Zhou M and Sun X: Matrine induces programmed cell death and regulates expression of relevant genes based on PCR array analysis in C6 glioma cells. Mol Biol Rep. 36:791–799. 2009. View Article : Google Scholar : PubMed/NCBI

45 

Yeung KT and Yang J: Epithelial-mesenchymal transition in tumor metastasis. Mol Oncol. 11:28–39. 2017. View Article : Google Scholar : PubMed/NCBI

46 

Lobb RJ, Lima LG and Möller A: Exosomes: Key mediators of metastasis and pre-metastatic niche formation. Semin Cell Dev Biol. Jan 8–2017.doi: 10.1016/j.semcdb.2017.01.004. View Article : Google Scholar : PubMed/NCBI

47 

Ren H, Zhang S, Ma H, Wang Y, Liu D, Wang X and Wang Z: Matrine reduces the proliferation and invasion of colorectal cancer cells via reducing the activity of p38 signaling pathway. Acta Biochim Biophys Sin (Shanghai). 46:1049–1055. 2014. View Article : Google Scholar : PubMed/NCBI

48 

Martinelli E, Morgillo F, Troiani T and Ciardiello F: Cancer resistance to therapies against the EGFR-RAS-RAF pathway: The role of MEK. Cancer Treat Rev. 53:61–69. 2017. View Article : Google Scholar : PubMed/NCBI

49 

Das AM, Pescatori M, Vermeulen CE, Rens JA, Seynhaeve AL, Koning GA, Eggermont AM and Ten Hagen TL: Melanomas prevent endothelial cell death under restrictive culture conditions by signaling through AKT and p38 MAPK/ERK-1/2 cascades. Oncoimmunology. 5:e12198262016. View Article : Google Scholar : PubMed/NCBI

50 

Zou X and Blank M: Targeting p38 MAP kinase signaling in cancer through post-translational modifications. Cancer Lett. 384:19–26. 2017. View Article : Google Scholar : PubMed/NCBI

51 

Li D, Chen J, Ye J, Zhai X, Song J, Jiang C, Wang J, Zhang H, Jia X and Zhu F: Anti-inflammatory effect of the six compounds isolated from Nauclea officinalis Pierrc ex Pitard, and molecular mechanism of strictosamide via suppressing the NF-kappaB and MAPK signaling pathway in LPS-induced RAW 264.7 macrophages. J Ethnopharmacol. 196:66–74. 2016. View Article : Google Scholar : PubMed/NCBI

52 

Lei YC, Lu CL, Chen L, Ge K, Yang LL, Li W and Wu YH: C5a/C5aR pathway is essential for up-regulating SphK1 expression through p38-MAPK activation in acute liver failure. World J Gastroenterol. 22:10148–10157. 2016. View Article : Google Scholar : PubMed/NCBI

53 

Lei H, Li X, Jing B, Xu H and Wu Y: Human S100A7 induces mature interleukin1α expression by RAGE-p38 MAPK-calpain1 pathway in psoriasis. PLoS One. 12:e01697882017. View Article : Google Scholar : PubMed/NCBI

54 

Liu Y, Zheng J, Zhang Y, Wang Z, Yang Y, Bai M and Dai Y: Fucoxanthin activates apoptosis via inhibition of PI3K/Akt/mTOR pathway and suppresses invasion and migration by restriction of p38-MMP-2/9 pathway in human glioblastoma cells. Neurochem Res. 41:2728–2751. 2016. View Article : Google Scholar : PubMed/NCBI

55 

Yu P, Liu Q, Liu K, Yagasaki K, Wu E and Zhang G: Matrine suppresses breast cancer cell proliferation and invasion via VEGF-Akt-NF-kappaB signaling. Cytotechnology. 59:219–229. 2009. View Article : Google Scholar : PubMed/NCBI

56 

Kwon CH, Moon HJ, Park HJ, Choi JH and Park DY: S100A8 and S100A9 promotes invasion and migration through p38 mitogen-activated protein kinase-dependent NF-κB activation in gastric cancer cells. Mol Cells. 35:226–234. 2013. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

August-2017
Volume 38 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Wu X, Zhou J, Cai D and Li M: Matrine inhibits the metastatic properties of human cervical cancer cells via downregulating the p38 signaling pathway. Oncol Rep 38: 1312-1320, 2017
APA
Wu, X., Zhou, J., Cai, D., & Li, M. (2017). Matrine inhibits the metastatic properties of human cervical cancer cells via downregulating the p38 signaling pathway. Oncology Reports, 38, 1312-1320. https://doi.org/10.3892/or.2017.5787
MLA
Wu, X., Zhou, J., Cai, D., Li, M."Matrine inhibits the metastatic properties of human cervical cancer cells via downregulating the p38 signaling pathway". Oncology Reports 38.2 (2017): 1312-1320.
Chicago
Wu, X., Zhou, J., Cai, D., Li, M."Matrine inhibits the metastatic properties of human cervical cancer cells via downregulating the p38 signaling pathway". Oncology Reports 38, no. 2 (2017): 1312-1320. https://doi.org/10.3892/or.2017.5787