Molecular mechanisms underlying the antimetastatic activity of bufalin (Review)

  • Authors:
    • Jie Wang
    • Yue Xia
    • Qingshong Zuo
    • Teng Chen
  • View Affiliations

  • Published online on: March 21, 2018     https://doi.org/10.3892/mco.2018.1591
  • Pages: 631-636
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Bufalin is a monomer compound extract from Chansu, which is a traditional Chinese medicine obtained from the skin and parotid venom glands of toads, such as Bufo bufo gargarizans Cantor and Bufo melanostictus Schneider. Chansu had been used in traditional Chinese medicine for >1,000 years due to its cardiac, anti-inflammatory and anticancer properties. Previous studies identified bufalin as the main anticancer compound of Chansu, and recent evidence has corroborated its anticancer properties. Bufalin inhibits cancer cell proliferation, induces cell cycle arrest, induces cancer cell apoptosis, inhibits neovascularization, induces cell differentiation, inhibits cancer metastasis and invasion, and enhances chemotherapeutic drug sensitivity. However, the function and mechanism of bufalin in metastatic cancer cells have not yet been expounded. The aim of the present review was to discuss the recent progress and prospects of bufalin in the prevention of cancer metastasis, particularly in inhibiting epithelial-to-mesenchymal transition.

Introduction

Cancer represents a major health concern worldwide. Although the mortality rate of malignant tumours has been controlled due to the scientific and technological advances in the field of oncology, it remains one of the deadliest diseases (1). The majority of cancer-related deaths may be attributed to the metastatic spread and invasion of cancer cells into other vital organs. During this process, cancer cells degrade the basement membrane and extracellular matrix (ECM) and migrate to adjacent areas, where they then invade the blood and/or lymphatic vessels and reach other organs or tissues via the circulation. Growth factors, ECM proteins, intercellular adhesions, the cytoskeleton and genes all participate in this process (2). Therefore, it is of great significance to further elucidate the molecular mechanisms underlying cancer development and design effective antitumour drugs to improve prevention and therapeutic strategies against cancer.

Epithelial-to-mesenchymal transition (EMT) is a process by which cells lose their epithelial characteristics and acquire a mesenchymal cell phenotype. EMT is important in embryonic development, chronic inflammation, tissue reconstruction, a variety of fibrotic diseases and cancer metastasis (3,4). During the process of EMT, the cell-to-cell and cell-to-matrix connections become weaker and the epithelial polarity acquires mesenchymal characteristics, promoting cancer cell migration and invasion of the surrounding matrix or other organs (57). Recently accumulated evidence indicates that EMT contributes to lymph node metastasis, distant metastasis, prognosis and chemoresistance of cancers (8,9).

During EMT, the expression of epithelial cell markers, such as E-cadherin, is downregulated, while mesenchymal cell markers, such as vimentin and N-cadherin, are upregulated. Transcription factors, such as Snail, Zeb and Twist, are also involved in these processes. It was also revealed that certain signalling pathways are involved in EMT, such as the transforming growth factor (TGF)-β signalling pathway (10), Wnt signalling pathway (11), Hedgehog signalling pathway (12), and Notch signalling pathway (13). The development of drugs or interventions to reverse the process of EMT has become an important target of cancer research (14,15).

Bufalin suppresses cancer metastasis by inhibiting EMT

Bufalin is a bioactive polyhydroxy steroid isolated from Venenum Bufonis, also referred to as Chansu, a well-known traditional Chinese herb. Chansu has been widely used in the clinical treatment of several malignancies in China (16,17). Recent studies demonstrated that bufalin exhibits anticancer activity against various cancers, such as breast cancer (18), osteosarcoma (19), colon cancer (20), lung cancer (21), pancreatic cancer (22), bladder cancer (23) and hepatocellular carcinoma (24). The underlying mechanisms include inhibiting cell proliferation (19), promoting cell apoptosis and autophagy (25,26), blocking the cell cycle (27), reversing multidrug resistance (28), and inhibiting EMT and cancer metastasis (24). Bufalin has been shown to affect several EMT signalling pathways.

Bufalin affects EMT by inhibiting TGF-β

The TGF-β family is a superfamily that regulates cell proliferation, apoptosis, the cell cycle, ECM transformation and tumour metastasis (29). The TGF-β family includes three isoform ligands, namely TGF-β1, TGF-β2 and TGF-β3, and two receptors, TβRI and TβRII. When the TGF-β ligand binds to the receptor, it leads to the phosphorylation of SMAD2 and SMAD3. Subsequently, SMAD4 is translocated into the nucleus and leads to the activation of target genes (30). Recent studies have found that the activation of TGF-β is involved in the EMT process and increases the potential of cancer metastasis. The EMT transcription factors targeted by TGF-β include Snail, two-handed zinc finger factors ZEB1 and ZEB2, and the basic helix-loop-helix Twist1 and Twist2 (3133).

It was reported that bufalin can inhibit EMT in cancer cells via the TGF-β pathway. Zhao et al (34) reported that bufalin downregulates the expression of TGF-β receptors and inhibits TGF-β-induced EMT and the migration of A549 lung cancer cells. That study demonstrated that, following treatment with TGF-β, the migratory ability of lung cancer cells increased, and the cell morphology resembled that of mesenchymal cells. When treated with bufalin, these phenomena were markedly suppressed. The expression of Twist2, ZEB2, SMAD2 and SMAD3 was also downregulated following treatment with bufalin. Further analysis revealed that the TGF-β receptors TβRI and TβRII were also downregulated in the presence of bufalin. When the phosphorylation of TβRI was blocked by the inhibitor SB431542, the TGF-β-induced EMT was attenuated, similar to treatment with bufalin. It was also demonstrated that bufalin inhibited the migration and invasion of human colon cancer HCT116 cells and increased the ability of cell adhesion. Following treatment with bufalin, the expression of TGF-β1, SMAD4 and E-cadherin increased, while the expression of phospho-SMAD3 decreased. These proteins may be associated with bufalin and can induce the nuclear translocation of β-catenin and prevent cancer cell EMT (35,36).

Bufalin affects EMT through the PI3K/AKT signalling pathway

The phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is involved in cell proliferation, cell cycle regulation and cell apoptosis. In addition, abnormal activation of AKT is associated with tumour occurrence and development. Overexpression of PI3K/AKT inhibits the apoptosis of cancer cells, and some chemotherapeutic drugs induce cell apoptosis by inhibiting the activation of AKT (37,38). It was also demonstrated that activated PI3K/AKT cell signalling may promote the degradation of ECM and reduce cell-cell adhesions, inducing EMT and thereby promoting the metastasis and invasion of malignant tumour cells (39). The overexpression of AKT promotes the expression of Twist and Snail, which are important in the activation of EMT. Treatment with an AKT inhibitor can restore the epithelial cell morphology to a polygonal shape and suppress the migration ability of cancer cells. While the expression of Twist and Snail was downregulated, E-cadherin expression was upregulated (40).

Wang et al (24) reported that bufalin suppresses liver cancer invasion and metastasis by downregulating the expression of the PI3K/AKT/mammalian target of rapamycin (mTOR) signalling pathway. That study demonstrated that, after treatment with bufalin, the liver/lung metastases were significantly reduced in mice with transplanted tumours. Furthermore, EMT was inhibited by bufalin, the expression of E-cadherin was upregulated, and the expression of N-cadherin, vimentin and Snail was downregulated. Moreover, the expression of TGF-β1 was inhibited after treatment with bufalin. It was also observed that bufalin can inhibit the expression of hypoxia-inducible factor-1α (HIF-1α) by suppressing the activation of the PI3K/AKT/mTOR pathway (41). Another study reported that bufalin can prevent hepatocellular carcinoma invasion and metastasis. Functional studies demonstrated that bufalin can inhibit matrix metalloproteinase (MMP)2 and MMP9 expression, as well as the expression of PI3K and the phosphorylation of AKT, thereby attenuating the expression of nuclear factor (NF)-κB (42).

Bufalin was also found to inhibit endometrial carcinoma cell migration and invasion. The expression of MMP9 and Snail was downregulated following treatment with bufalin, while the expression of E-cadherin was upregulated. Functional studies demonstrated that bufalin inhibits cervical tumourigenesis and metastasis by modulating α2/β5/FAK cell signalling and affecting the expression of PI3K/AKT. Integrins α2/β5 and downstream related genes FAK, pFAK, pGSK3β, AKT1 and p-AKT1 were all downregulated following treatment with bufalin (43).

Bufalin affects EMT through the Wnt/β-catenin signalling pathway

Wnt signalling comprises a group of signal transduction pathways consisting of proteins that transmit signals into the cell through cell surface receptors. There are three characterized Wnt signalling pathways: The canonical Wnt pathway, the non-canonical planar cell polarity pathway, and the non-canonical Wnt/calcium pathway (44). The Wnt/β-catenin pathway is crucial for cellular maintenance and development, such as cell cycle progression, apoptosis, differentiation, migration and proliferation (45). The overstimulation of these pathways is closely associated with cancer development. During the development of cancer, the phosphorylation and/or nuclear localization of β-catenin increases, and the Wnt/β-catenin pathway is activated, increasing the migration and invasion ability of cancer cells (46). Furthermore, the Wnt/β-catenin pathway induces EMT by activating Twist1, ZEB1, Snail and Slug (47).

Gai et al (48) observed that bufalin inhibited the proliferation, migration and invasion of the hepatocellular carcinoma cell line BEL-7402. Upon investigating the underlying mechanism, they found that bufalin suppressed the phosphorylation of the GSK-3β Ser9 site in BEL-7402 cells and decreased the expression of cyclin D1, MMP7 and cyclooxygenase-2. They also found that bufalin inhibited the transfer of β-catenin to the nucleus, which is a key step in the Wnt/β-catenin signalling pathway.

Bufalin inhibits EMT through the Hedgehog signalling pathway

The Hedgehog (Hh) signalling pathway is highly conserved and is essential for the development of the normal embryo, particularly during early embryogenesis and morphogenesis of specific organs and tissues (49). The Hh pathway is usually silenced in most adult tissues; however, after injury, the pathway is reactivated to promote the repair and regeneration of cells. Furthermore, aberrant Hh signalling has been detected in a number of human cancers and has been implicated in tumourigenesis (50,51). When Hh signalling is silenced, the receptor Patched (PTCH1) binds the receptor Smoothened (SMO), inhibiting SMO and its downstream pathway activity. When PTCH1 binds its ligand, Sonic Hedgehog (SHH), SMO is activated and, subsequently, the glioma-associated oncogene Gli transcription factor is activated (52). Studies have found that Gli family members are associated with cancer cell EMT and metastasis, and Gli is also associated with the Hh signalling pathway (51,53).

Sheng et al (54) reported that bufalin was able to inhibit liver cancer cell EMT and ECM degradation by affecting the Gli1 and Gli3 expression of the Hh signalling pathway. Bufalin inhibited the expression of MMP2, MMP9, β-catenin and vascular endothelial growth factor in liver cancer cells and upregulated E-cadherin expression. Another study also demonstrated that bufalin was able to suppress cancer stem-like cells in gemcitabine-resistant pancreatic cancer via Hh signalling. Bufalin was also shown to inhibit the colony formation of pancreatic cancer cells and reduce tumourigenesis in nude mice. Western blotting and immunohistochemical results revealed that CD24 and epithelial-specific antigen levels were downregulated after treatment with bufalin. Bufalin was also shown to inhibit metastasis in nude mice injected with tumour cells via the tail vein. Moreover, Hh signalling was found to be suppressed in bufalintreated cells (22).

Other antimetastatic effects of bufalin

Bufalin inhibits NF-κB activation. NF-κB was first identified by Dr Ranjan Sen via its interaction with an 11-base pair sequence in the immunoglobulin light-chain enhancer in B cells (55). NF-κB plays an important role in immune response, as well as in cancer initiation and progression. When NF-κB is activated, preneoplastic and malignant cells exhibit increased anti-apoptotic ability. NF-κB is also implicated in tumour angiogenesis and invasiveness. Thus, NF-κB and its pathway are promising targets in anticancer therapy (56). It was reported that bufalin can inhibit hepatocellular carcinoma invasion and metastasis. Functional studies demonstrated that bufalin inhibited the expression of MMP2, MMP9 and PI3K and suppressed the phosphorylation of AKT, which was associated with a reduction in the level of NF-κB (42).

Bufalin modulates the activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signalling pathway. MAPKs are serine-threonine kinases that are involved in diverse biological activities, such as cell proliferation, differentiation, survival, death and transformation (57). The MAPK family includes ERK, p38 and c-Jun NH2-terminal kinase (JNK). Both extracellular and intracellular stimuli can promote the activation of MAPK pathways, such as peptide growth factors, cytokines, hormones, oxidative stress and endoplasmic reticulum stress (58). A number of studies have demonstrated that the abnormal expression of MAPK signalling pathways is important in tumour development. The ERK pathway also increases the expression of MMPs, promotes the degradation of ECM proteins, and enhances the invasion ability of cancer cells (59,60).

Hong et al (23) reported that bufalin attenuated the migratory and invasive abilities of bladder cancer cells. Following treatment with bufalin, the expression of transepithelial electrical resistance increased, which promoted the expression of tight junctions. Bufalin also inhibits the expression of MMP2 and MMP9, while increasing the expression of metalloproteinase inhibitor. All these molecules are associated with the activation of the ERK pathway. Chueh et al (61) also found that bufalin inhibited the migration and invasion of human osteosarcoma U-2 OS cells and reduced the levels of MAPKs, such as JNK1/2 and ERK1/2.

Bufalin prevents cell migration by regulating the expression of miRNAs. MicroRNAs (miRNAs) are non-coding RNAs, ~22 nucleotides in length and highly conserved. miRNAs can regulate gene expression by binding to target sequences in mRNAs to induce mRNA degradation or suppress translation. miRNAs regulate various cellular processes, such as metastasis, proliferation and chemosensitivity. Studies have demonstrated that a number of malignant tumours have disrupted regulation of miRNAs that exert anticancer or tumour-promoting effects (6265). miRNA profiling has become a diagnostic and prognostic marker as well as a therapeutic target for cancer (66). Qiu et al (67) demonstrated that bufalin can inhibit the migration of human colon cancer cells (HCT116) and human umbilical vein endothelial cells (HUVECs). They observed that miR-497 was upregulated in human colorectal cancer HCT116 cells treated with different concentrations of bufalin. In addition, bufalin was found to enhance the expression of the tumour suppressor miR-497 in nude mice.

In conclusion, bufalin is a potential polygenic and multi-target anticancer agent (Fig. 1) that can inhibit EMT by regulating the expression of TGF-β, PI3K/AKT, Hh and Wnt/β-catenin signalling pathways, thereby preventing metastasis. Bufalin also inhibits cancer metastasis by suppressing NF-ĸB activation and regulating the MAPK/ERK signalling pathway, as well as the expression of certain miRNAs. All these signalling pathways are interrelated; for example, bufalin modulates the PI3K/AKT signalling pathway, and PI3K/AKT activity in turn regulates the expression of NF-ĸB in hepatocellular carcinoma (42). However, the study of the anticancer and antimetastatic properties of bufalin is in its initial phases, and the underlying molecular mechanism remains unknown. Studies are currently limited to fundamental research, and several more studies are required before bufalin can be used in a clinical setting. However, with additional studies investigating the effect of bufalin on oncogenic cell signalling pathways or targets, it has the potential to become a drug for targeting cancer metastasis.

Acknowledgements

Not applicable.

Funding

This study was supported by the Health System Independent Innovation Science Foundation of Shanghai Putuo District (grant no. 2013PTKW002), the Foundation of Key Clinical Specialty of Shanghai Putuo District (grant no. 2016PTZK01), and the Scientific Research Funds of Sixth People's Hospital of Shanghai Medical Group (grant no. 15-LY-01).

Availability of data and materials

The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

Authors' contributions

JW and TC made substantial contributions to the conception and design of the study, and wrote the manuscript, JW, YX and Q-SZ performed literatures search regarding bufalin anti-cancer activity. The final version of the manuscript has been read and approved by all authors.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Siegel RL, Miller KD and Jemal A: Cancer Statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI

2 

Coghlin C and Murray GI: Current and emerging concepts in tumour metastasis. J Pathol. 222:1–15. 2010. View Article : Google Scholar : PubMed/NCBI

3 

Low WHH, Seet W, A S R, Ng KK, H J, Dan SP, Teng CL, Lee VKM, Chua SS, My FA, et al: Community-based cardiovascular Risk Factors Intervention Strategies (CORFIS) in managing hypertension: A pragmatic non-randomised controlled trial. Med J Malaysia. 68:129–135. 2013.PubMed/NCBI

4 

Zeisberg M and Neilson EG: Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 119:1429–1437. 2009. View Article : Google Scholar : PubMed/NCBI

5 

Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009. View Article : Google Scholar : PubMed/NCBI

6 

Lee MY, Chou CY, Tang MJ and Shen MR: Epithelial-mesenchymal transition in cervical cancer: Correlation with tumor progression, epidermal growth factor receptor overexpression, and snail up-regulation. Clin Cancer Res. 14:4743–4750. 2008. View Article : Google Scholar : PubMed/NCBI

7 

Garg M: Epithelial, mesenchymal and hybrid epithelial/mesenchymal phenotypes and their clinical relevance in cancer metastasis. Expert Rev Mol Med. 19:e32017. View Article : Google Scholar : PubMed/NCBI

8 

Piva F, Giulietti M, Santoni M, Occhipinti G, Scarpelli M, Lopez-Beltran A, Cheng L, Principato G and Montironi R: Epithelial to Mesenchymal Transition in Renal Cell Carcinoma: Implications for Cancer Therapy. Mol Diagn Ther. 20:111–117. 2016. View Article : Google Scholar : PubMed/NCBI

9 

Okubo K, Uenosono Y, Arigami T, Yanagita S, Matsushita D, Kijima T, Amatatsu M, Uchikado Y, Kijima Y, Maemura K, et al: Clinical significance of altering epithelial-mesenchymal transition in metastatic lymph nodes of gastric cancer. Gastric Cancer. 20:802–810. 2017. View Article : Google Scholar : PubMed/NCBI

10 

He H, Kuriyan AE, Su CW, Mahabole M, Zhang Y, Zhu YT, Flynn HW, Parel JM and Tseng SC: Inhibition of Proliferation and Epithelial Mesenchymal Transition in Retinal Pigment Epithelial Cells by Heavy Chain-Hyaluronan/Pentraxin 3. Sci Rep. 7:437362017. View Article : Google Scholar : PubMed/NCBI

11 

Yu M, Ting DT, Stott SL, Wittner BS, Ozsolak F, Paul S, Ciciliano JC, Smas ME, Winokur D, Gilman AJ, et al: RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. Nature. 487:510–513. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Xu X, Su B, Xie C, Wei S, Zhou Y, Liu H, Dai W, Cheng P, Wang F, Xu X, et al: Sonic hedgehog-Gli1 signaling pathway regulates the epithelial mesenchymal transition (EMT) by mediating a new target gene, S100A4, in pancreatic cancer cells. PLoS One. 9:e964412014. View Article : Google Scholar : PubMed/NCBI

13 

Bao B, Wang Z, Ali S, Kong D, Li Y, Ahmad A, Banerjee S, Azmi AS, Miele L and Sarkar FH: Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells. Cancer Lett. 307:26–36. 2011. View Article : Google Scholar : PubMed/NCBI

14 

Kaushik N, Kim MJ, Kim RK, Kumar Kaushik N, Seong KM, Nam SY and Lee SJ: Low-dose radiation decreases tumor progression via the inhibition of the JAK1/STAT3 signaling axis in breast cancer cell lines. Sci Rep. 7:433612017. View Article : Google Scholar : PubMed/NCBI

15 

Mobley RJ, Raghu D, Duke LD, Abell-Hart K, Zawistowski JS, Lutz K, Gomez SM, Roy S, Homayouni R, Johnson GL, et al: MAP3K4 Controls the Chromatin Modifier HDAC6 during Trophoblast Stem Cell Epithelial-to-Mesenchymal Transition. Cell Reports. 18:2387–2400. 2017. View Article : Google Scholar : PubMed/NCBI

16 

Qiu DZ, Zhang ZJ, Wu WZ and Yang YK: Bufalin, a component in Chansu, inhibits proliferation and invasion of hepatocellular carcinoma cells. BMC Complement Altern Med. 13:1852013. View Article : Google Scholar : PubMed/NCBI

17 

Li C, Hashimi SM, Cao S, Mellick AS, Duan W, Good D and Wei MQ: The mechanisms of chansu in inducing efficient apoptosis in colon cancer cells. Evid Based Complement Alternat Med. 2013:8490542013.PubMed/NCBI

18 

Zou Z, Luo X, Nie P, Wu B, Zhang T, Wei Y, Wang W, Geng G, Jiang J and Mi Y: Inhibition of SRC-3 enhances sensitivity of human cancer cells to histone deacetylase inhibitors. Biochem Biophys Res Commun. 478:227–233. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Zhang J, Sha J, Zhou Y, Han K, Wang Y, Su Y, Yin X, Hu H and Yao Y: Bufalin Inhibits Proliferation and Induces Apoptosis in Osteosarcoma Cells by Downregulating MicroRNA-221. Evid Based Complement Alternat Med. 2016:73194642016. View Article : Google Scholar : PubMed/NCBI

20 

Wang J, Chen C, Wang S, Zhang Y, Yin P, Gao Z, Xu J, Feng D, Zuo Q, Zhao R, et al: Bufalin Inhibits HCT116 Colon Cancer Cells and Its Orthotopic Xenograft Tumor in Mice Model through Genes Related to Apoptotic and PTEN/AKT Pathways. Gastroenterol Res Pract. 2015:4571932015. View Article : Google Scholar : PubMed/NCBI

21 

Sun P, Feng LX, Zhang DM, Liu M, Liu W, Mi T, Wu WY, Jiang BH, Yang M, Hu LH, et al: Bufalin derivative BF211 inhibits proteasome activity in human lung cancer cells in vitro by inhibiting β1 subunit expression and disrupting proteasome assembly. Acta Pharmacol Sin. 37:908–918. 2016. View Article : Google Scholar : PubMed/NCBI

22 

Wang H, Ning Z, Li Y, Zhu X and Meng Z: Bufalin suppresses cancer stem-like cells in gemcitabine-resistant pancreatic cancer cells via Hedgehog signaling. Mol Med Rep. 14:1907–1914. 2016. View Article : Google Scholar : PubMed/NCBI

23 

Hong SH, Kim GY, Chang YC, Moon SK, Kim WJ and Choi YH: Bufalin prevents the migration and invasion of T24 bladder carcinoma cells through the inactivation of matrix metalloproteinases and modulation of tight junctions. Int J Oncol. 42:277–286. 2013. View Article : Google Scholar : PubMed/NCBI

24 

Wang H, Zhang C, Xu L, Zang K, Ning Z, Jiang F, Chi H, Zhu X and Meng Z: Bufalin suppresses hepatocellular carcinoma invasion and metastasis by targeting HIF-1α via the PI3K/AKT/mTOR pathway. Oncotarget. 7:20193–20208. 2016.PubMed/NCBI

25 

Liu M, Feng LX, Sun P, Liu W, Wu WY, Jiang BH, Yang M, Hu LH, Guo DA and Liu X: A Novel Bufalin Derivative Exhibited Stronger Apoptosis-Inducing Effect than Bufalin in A549 Lung Cancer Cells and Lower Acute Toxicity in Mice. PLoS One. 11:e01597892016. View Article : Google Scholar : PubMed/NCBI

26 

Shen S, Zhang Y, Wang Z, Liu R and Gong X: Bufalin induces the interplay between apoptosis and autophagy in glioma cells through endoplasmic reticulum stress. Int J Biol Sci. 10:212–224. 2014. View Article : Google Scholar : PubMed/NCBI

27 

Liu X, Xiao XY, Shou QY, Yan JF, Chen L, Fu HY and Wang JC: Bufalin inhibits pancreatic cancer by inducing cell cycle arrest via the c-Myc/NF-κB pathway. J Ethnopharmacol. 193:538–545. 2016. View Article : Google Scholar : PubMed/NCBI

28 

Zhai X, Lu J, Wang Y, Fang F, Li B and Gu W: Reversal effect of bufalin on multidrug resistance in K562/VCR vincristine-resistant leukemia cell line. J Tradit Chin Med. 34:678–683. 2014. View Article : Google Scholar : PubMed/NCBI

29 

Heldin CH, Vanlandewijck M and Moustakas A: Regulation of EMT by TGFβ in cancer. FEBS Lett. 586:1959–1970. 2012. View Article : Google Scholar : PubMed/NCBI

30 

Gaarenstroom T and Hill CS: TGF-β signaling to chromatin: How Smads regulate transcription during self-renewal and differentiation. Semin Cell Dev Biol. 32:107–118. 2014. View Article : Google Scholar : PubMed/NCBI

31 

Lombaerts M, van Wezel T, Philippo K, Dierssen JW, Zimmerman RM, Oosting J, van Eijk R, Eilers PH, van de Water B, Cornelisse CJ, et al: E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. Br J Cancer. 94:661–671. 2006. View Article : Google Scholar : PubMed/NCBI

32 

Kahata K, Dadras MS and Moustakas A: TGF-β Family Signaling in Epithelial Differentiation and Epithelial-Mesenchymal Transition. Cold Spring Harb Perspect Biol. 10:0221942018. View Article : Google Scholar

33 

Ikushima H and Miyazono K: Cellular context-dependent ‘colors’ of transforming growth factor-beta signaling. Cancer Sci. 101:306–312. 2010. View Article : Google Scholar : PubMed/NCBI

34 

Zhao L, Liu S, Che X, Hou K, Ma Y, Li C, Wen T, Fan Y, Hu X, Liu Y, et al: Bufalin inhibits TGF-β-induced epithelial-to-mesenchymal transition and migration in human lung cancer A549 cells by downregulating TGF-β receptors. Int J Mol Med. 36:645–652. 2015. View Article : Google Scholar : PubMed/NCBI

35 

Zhao R, Yu H, Shi X, Qiu Y, Qian Y and Yin P: The influence of Bufalin on TGF-β1-induced epithelial mesenchymal transition in HCT-116 cells. Surg Res N Tech. 4:217–222. 2015.

36 

Wang S, Lin J, Xing L and Chen T: Mechanism of Bufalin inhibiting invasion of human colon cancer HCT116 cells. China J Cancer Prev Treat. 23:52016.

37 

Wang SQ, Wang C, Chang LM, Zhou KR, Wang JW, Ke Y, Yang DX, Shi HG, Wang R, Shi XL, et al: Geridonin and paclitaxel act synergistically to inhibit the proliferation of gastric cancer cells through ROS-mediated regulation of the PTEN/PI3K/Akt pathway. Oncotarget. 7:72990–73002. 2016.PubMed/NCBI

38 

Wang R, Song Y, Liu X, Wang Q, Wang Y, Li L, Kang C and Zhang Q: UBE2C induces EMT through Wnt/β catenin and PI3K/Akt signaling pathways by regulating phosphorylation levels of Aurora-A. Int J Oncol. 50:1116–1126. 2017. View Article : Google Scholar : PubMed/NCBI

39 

Yoo YA, Kang MH, Lee HJ, Kim BH, Park JK, Kim HK, Kim JS and Oh SC: Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer. Cancer Res. 71:7061–7070. 2011. View Article : Google Scholar : PubMed/NCBI

40 

Hong KO, Kim JH, Hong JS, Yoon HJ, Lee JI, Hong SP and Hong SD: Inhibition of Akt activity induces the mesenchymal-to-epithelial reverting transition with restoring E-cadherin expression in KB and KOSCC-25B oral squamous cell carcinoma cells. J Exp Clin Cancer Res. 28:282009. View Article : Google Scholar : PubMed/NCBI

41 

Zhang L, Huang G, Li X, Zhang Y, Jiang Y, Shen J, Liu J, Wang Q, Zhu J, Feng X, et al: Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor-1α in hepatocellular carcinoma. BMC Cancer. 13:1–9. 2013. View Article : Google Scholar : PubMed/NCBI

42 

Chen YY, Lu HF, Hsu SC, Kuo CL, Chang SJ, Lin JJ, Wu PP, Liu JY, Lee CH, Chung JG, et al: Bufalin inhibits migration and invasion in human hepatocellular carcinoma SK-Hep1 cells through the inhibitions of NF-kB and matrix metalloproteinase-2/-9-signaling pathways. Environ Toxicol. 30:74–82. 2015. View Article : Google Scholar : PubMed/NCBI

43 

Liu F, Tong D, Li H, Liu M, Li J, Wang Z and Cheng X: Bufalin enhances antitumor effect of paclitaxel on cervical tumorigenesis via inhibiting the integrin α2/β5/FAK signaling pathway. Oncotarget. 7:8896–8907. 2016.PubMed/NCBI

44 

Nusse R and Varmus HE: Wnt genes. Cell. 69:1073–1087. 1992. View Article : Google Scholar : PubMed/NCBI

45 

Serman L, Martic Nikuseva T, Serman A and Vranic S: Epigenetic alterations of the Wnt signaling pathway in cancer: A mini review. Bosn J Basic Med Sci. 14:191–194. 2014. View Article : Google Scholar : PubMed/NCBI

46 

Ma Y, Zhu B, Liu X, Yu H, Yong L, Liu X, Shao J and Liu Z: Inhibition of oleandrin on the proliferation show and invasion of osteosarcoma cells in vitro by suppressing Wnt/β-catenin signaling pathway. J Exp Clin Cancer Res. 34:1152015. View Article : Google Scholar : PubMed/NCBI

47 

Kim K, Lu Z and Hay ED: Direct evidence for a role of β-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol Int. 26:463–476. 2002. View Article : Google Scholar : PubMed/NCBI

48 

Gai JQ, Sheng X, Qin JM, Sun K, Zhao W and Ni L: The effect and mechanism of bufalin on regulating hepatocellular carcinoma cell invasion and metastasis via Wnt/β-catenin signaling pathway. Int J Oncol. 48:338–348. 2016. View Article : Google Scholar : PubMed/NCBI

49 

Nüsslein-Volhard C and Wieschaus E: Mutations affecting segment number and polarity in Drosophila. Nature. 287:795–801. 1980. View Article : Google Scholar : PubMed/NCBI

50 

McMillan R and Matsui W: Molecular pathways: The hedgehog signaling pathway in cancer. Clin Cancer Res. 18:4883–4888. 2012. View Article : Google Scholar : PubMed/NCBI

51 

Chun HW and Hong R: Significance of the hedgehog pathway-associated proteins Gli-1 and Gli-2 and the epithelial-mesenchymal transition-associated proteins Twist and E-cadherin in hepatocellular carcinoma. Oncol Lett. 12:1753–1762. 2016. View Article : Google Scholar : PubMed/NCBI

52 

Hui CC and Angers S: Gli proteins in development and disease. Annu Rev Cell Dev Biol. 27:513–537. 2011. View Article : Google Scholar : PubMed/NCBI

53 

Chong Y, Tang D, Gao J, Jiang X, Xu C, Xiong Q, Huang Y, Wang J, Zhou H, Shi Y, et al: Galectin-1 induces invasion and the epithelial-mesenchymal transition in human gastric cancer cells via non-canonical activation of the hedgehog signaling pathway. Oncotarget. 7:83611–83626. 2016. View Article : Google Scholar : PubMed/NCBI

54 

Sheng X, Sun X, Sun K, Sui H, Qin J and Li Q: Inhibitory effect of bufalin combined with Hedgehog signaling pathway inhibitors on proliferation and invasion and metastasis of liver cancer cells. Int J Oncol. 49:1513–1524. 2016. View Article : Google Scholar : PubMed/NCBI

55 

Sen R and Baltimore D: Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 1986. 46: 705–716. J Immunol. 177:7485–7496. 2006.PubMed/NCBI

56 

Karin M: NF-kappaB and cancer: Mechanisms and targets. Mol Carcinog. 45:355–361. 2006. View Article : Google Scholar : PubMed/NCBI

57 

Torii S, Yamamoto T, Tsuchiya Y and Nishida E: ERK MAP kinase in G cell cycle progression and cancer. Cancer Sci. 97:697–702. 2006. View Article : Google Scholar : PubMed/NCBI

58 

Kim EK and Choi EJ: Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 1802:396–405. 2010. View Article : Google Scholar : PubMed/NCBI

59 

Huang C, Jacobson K and Schaller MD: MAP kinases and cell migration. J Cell Sci. 117:4619–4628. 2004. View Article : Google Scholar : PubMed/NCBI

60 

Cong Q, Jia H, Li P, Qiu S, Yeh J, Wang Y, Zhang ZL, Ao J, Li B and Liu H: p38α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner. Sci Rep. 7:459642017. View Article : Google Scholar : PubMed/NCBI

61 

Chueh FS, Chen YY, Huang AC, Ho HC, Liao CL, Yang JS, Kuo CL and Chung JG: Bufalin-inhibited migration and invasion in human osteosarcoma U-2 OS cells is carried out by suppression of the matrix metalloproteinase-2, ERK, and JNK signaling pathways. Environ Toxicol. 29:21–29. 2014. View Article : Google Scholar : PubMed/NCBI

62 

Krol J, Loedige I and Filipowicz W: The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 11:597–610. 2010. View Article : Google Scholar : PubMed/NCBI

63 

Othman N, In LL, Harikrishna JA and Hasima N: Bcl-xL silencing induces alterations in hsa-miR-608 expression and subsequent cell death in A549 and SK-LU1 human lung adenocarcinoma cells. PLoS One. 8:e817352013. View Article : Google Scholar : PubMed/NCBI

64 

Ho CS, Yap SH, Phuah NH, In LL and Hasima N: MicroRNAs associated with tumour migration, invasion and angiogenic properties in A549 and SK-Lu1 human lung adenocarcinoma cells. Lung Cancer. 83:154–162. 2014. View Article : Google Scholar : PubMed/NCBI

65 

Li Y, Su J, Li F, Chen X and Zhang G: MiR-150 regulates human keratinocyte proliferation in hypoxic conditions through targeting HIF-1α and VEGFA: Implications for psoriasis treatment. PLoS One. 12:e01754592017. View Article : Google Scholar : PubMed/NCBI

66 

Mohammadi A, Mansoori B and Baradaran B: Regulation of miRNAs by herbal medicine: An emerging field in cancer therapies. Biomed Pharmacother. 86:262–270. 2017. View Article : Google Scholar : PubMed/NCBI

67 

Qiu YY, Hu Q, Tang QF, Feng W, Hu SJ, Liang B, Peng W and Yin PH: MicroRNA-497 and bufalin act synergistically to inhibit colorectal cancer metastasis. Tumour Biol. 35:2599–2606. 2014. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

May 2018
Volume 8 Issue 5

Print ISSN: 2049-9450
Online ISSN:2049-9469

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Wang, J., Xia, Y., Zuo, Q., & Chen, T. (2018). Molecular mechanisms underlying the antimetastatic activity of bufalin (Review). Molecular and Clinical Oncology, 8, 631-636. https://doi.org/10.3892/mco.2018.1591
MLA
Wang, J., Xia, Y., Zuo, Q., Chen, T."Molecular mechanisms underlying the antimetastatic activity of bufalin (Review)". Molecular and Clinical Oncology 8.5 (2018): 631-636.
Chicago
Wang, J., Xia, Y., Zuo, Q., Chen, T."Molecular mechanisms underlying the antimetastatic activity of bufalin (Review)". Molecular and Clinical Oncology 8, no. 5 (2018): 631-636. https://doi.org/10.3892/mco.2018.1591