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Farooqi, A.A.; Rakhmetova, V.S.; Kapanova, G.; Tashenova, G.; Tulebayeva, A.; Akhenbekova, A.; Ibekenov, O.; Turgambayeva, A.; Xu, B. Bufalin-Mediated Regulation of Cell Signaling Pathways in Cancers. Encyclopedia. Available online: https://encyclopedia.pub/entry/42478 (accessed on 17 July 2025).
Farooqi AA, Rakhmetova VS, Kapanova G, Tashenova G, Tulebayeva A, Akhenbekova A, et al. Bufalin-Mediated Regulation of Cell Signaling Pathways in Cancers. Encyclopedia. Available at: https://encyclopedia.pub/entry/42478. Accessed July 17, 2025.
Farooqi, Ammad Ahmad, Venera S. Rakhmetova, Gulnara Kapanova, Gulnara Tashenova, Aigul Tulebayeva, Aida Akhenbekova, Onlassyn Ibekenov, Assiya Turgambayeva, Baojun Xu. "Bufalin-Mediated Regulation of Cell Signaling Pathways in Cancers" Encyclopedia, https://encyclopedia.pub/entry/42478 (accessed July 17, 2025).
Farooqi, A.A., Rakhmetova, V.S., Kapanova, G., Tashenova, G., Tulebayeva, A., Akhenbekova, A., Ibekenov, O., Turgambayeva, A., & Xu, B. (2023, March 23). Bufalin-Mediated Regulation of Cell Signaling Pathways in Cancers. In Encyclopedia. https://encyclopedia.pub/entry/42478
Farooqi, Ammad Ahmad, et al. "Bufalin-Mediated Regulation of Cell Signaling Pathways in Cancers." Encyclopedia. Web. 23 March, 2023.
Bufalin-Mediated Regulation of Cell Signaling Pathways in Cancers
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This entry is adapted from the peer-reviewed paper 10.3390/molecules28052231

Bufalin is a pharmacologically active molecule isolated from the skin of the toad Bufo gargarizans or Bufo melanostictus. Bufalin has characteristically unique properties to regulate multiple molecular targets and can be used to harness multi-targeted therapeutic regimes against different cancers. There is burgeoning evidence related to functional roles of signaling cascades in carcinogenesis and metastasis. Bufalin has been reported to regulate pleiotropically a myriad of signal transduction cascades in various cancers. Importantly, bufalin mechanistically regulated JAK/STAT, Wnt/β-Catenin, mTOR, TRAIL/TRAIL-R, EGFR, and c-MET pathways. Furthermore, bufalin-mediated modulation of non-coding RNAs in different cancers has also started to gain tremendous momentum. Similarly, bufalin-mediated targeting of tumor microenvironments and tumor macrophages is an area of exciting research and we have only started to scratch the surface of the complicated nature of molecular oncology. Cell culture studies and animal models provide proof-of-concept for the impetus role of bufalin in the inhibition of carcinogenesis and metastasis.

cancer apoptosis cell signaling bufalin metastasis

1. Introduction

Recent advancements in next-generation sequencing and multi-omics analyses have demonstrated how crosstalk of different signaling cascades can result in the formation of a complex web of circuitries within cancer cells that, if fully mapped, can be utilized for more precisely targeted therapies. A wealth of information shows that intracellular signaling is dependent on a multitude of signaling pathways that have evolved for tightly orchestrated and dynamic cellular responses. Furthermore, many signaling cascades interact with each other and form multi-dimensional networks that regulate the integration of numerous inputs to generate sophisticated cellular responses. Seminal research works have uncovered key discoveries in fundamental biology and different types of cellular signaling pathways. Deregulation of transduction cascades not only promoted cancer progression but also fueled the spread of therapeutically resistant and metastatically competent cancer cells to distant organs for the development of secondary tumors [1][2][3][4][5][6].
Natural product research in preclinical studies has generated valuable literature related to inhibition of carcinogenesis and metastasis [7][8][9]. Small molecules are pharmacological tools of considerable value for mechanistic dissection of highly intricate biological processes and identification of possible therapeutic interventions. Chemoproteomic workflows have enabled additional multiplexing in research methodologies, which will be valuable for assessing target identification and compound selectivity. The metamorphosis of preclinical research has widened the avenues of effective clinical research. Mechanistic insights gleaned over decades of ground-breaking discoveries have sparked unprecedented research interests in pharmacological evaluation of natural products in the amelioration and remedy of different diseases [10][11].
Bufalin is a pharmacologically active molecule isolated from the skin of the toad Bufo gargarizans or Bufo melanostictus. A substantial volume of conceptual knowledge has been added to the rapidly evolving field of medicinal research associated with the pharmaceutical significance of bufalin. Cancer chemopreventive effects of bufalin have been reviewed previously in various useful and informative review articles [12][13][14][15][16].

2. Regulation of JAK/STAT Pathway by Bufalin

A look through a scientific lens indicates that in a burst of research activity, principally published between 1991 and 1994, the cast of JAK-STAT family members and the trajectories of the pathway were mapped to a greater extent. Many functional and structural protein studies and physiological studies on the proteins of the pathway have been reported. The Janus kinase (JAK)/signal transducers and activators of transcription (STATs) transduction pathway is an intracellular signaling cascade required for response to many extracellular ligands. Essentially, phosphorylation induces JAK activation and consequently these kinases phosphorylate intracellular components of the receptors, which allows the recruitment of STAT proteins [17][18][19][20][21]. Genome-wide analyses have yielded a number of discoveries about the biology of STAT proteins. In this section, the most recent evidence has been gathered to summarize multi-step regulation of JAK/STAT pathways by bufalin in different cancers.
Cancer-associated fibroblasts (CAFs) have a critical role in tumor microenvironment. CAF-conditioned media-treated colorectal cancer cells expressed high levels of p-STAT3 and matrix metalloproteinase-2, whereas low levels of E-cadherin were found in hyperactive STAT3-expressing cancer cells. Bufalin blocked CAF-induced invasion and metastasis of colorectal cancer cells by inactivation of the STAT3 pathway. Intraperitoneal injections of bufalin efficiently suppressed hepatic metastatic nodules in mice injected with HCT116 and CAF cells in the spleen (shown in Figure 1) [22].
Figure 1. (A) JAK/STAT signaling triggered the upregulation of Bcl2, Mcl-1, survivin, and VEGF. JAK2 phosphorylated STAT3 and promoted nuclear accumulation of STAT3 proteins. (B,C) Bufalin inhibited the activation of JAK2 and STAT3. (D) Acetyl-bufalin inhibited tumor formation in mice. Bufalin also inhibited angiogenesis and liver metastasis.

3. Regulation of AKT/mTOR Pathway by Bufalin

mTOR protein kinase occupies a central role in the nexus of many signaling cascades and plays essential roles in the regulation of different mechanisms. Protein synthesis is a resource-intensive and energy-intensive process in the rapidly growing cells. It is thus tightly controlled by mTORC1, which promotes protein synthesis by phosphorylation of 4E-BPs (eukaryotic initiation factor 4E-binding proteins) and p70S6K1 (S6 kinase 1). In its unphosphorylated state, 4E-BP1 suppressed translation by binding and sequestration of eIF4E (eukaryotic translation initiation factor 4E), an essential constituent of the eIF4F cap-binding complex [23]. mTORC1 regulated cap-dependent translation of mRNAs by direct phosphorylation of the inhibitors of eIF4E: namely, 4E-BP1 and 4E-BP2. TSC2 formed a heterodimeric complex with TSC1 and inhibited mTORC1. However, phosphorylation of TSC2 at the 1462nd threonine by AKT inhibited its GAP activity for RHEB, which therefore remained in a GTP-bound active state and activated mTORC1. AMPK inhibited mTORC1 by phosphorylation of RAPTOR at serine-792 and TSC2 at serine-1387 which promoted the inhibitory functions of TSC1-TSC2 complexes [24][25]. Here, the researchers offer an overview of current advancements in the field regarding the regulation of the AKT/mTOR pathway by bufalin.
Importantly, bufalin significantly reduced the phosphorylation levels of mTOR and S6K. Furthermore, HIF-1α levels were significantly reduced by bufalin. HIF-1α overexpression attenuated the inhibitory effects of bufalin on ovarian cancer cells. Intraperitoneal injections of bufalin proficiently induced regression of tumor xenografts in rodent models inoculated with PA-1 cells [26].
Cbl-b efficiently promoted autophagic pathway activity induced by bufalin through the inactivation of mTOR and activation of ERK1/2. mTOR has been reported to negatively regulate autophagy. Therefore, once activated by AKT/PKB, mTOR inhibited autophagy by enhancing the phosphorylation of p70S6K. Bufalin effectively reduced p-AKT, p-mTOR, and p-p70S6K (Figure 2) [27]. Together, these details indicate that inactivation of AKT/mTOR/p70S6K cascades and functionalization of the ERK pathway are involved in the activation of the autophagic pathway in bufalin-treated MGC803 cancer cells.
Figure 2. Bufalin mediated inactivation of AKT/mTOR pathway. Bufalin effectively reduced p-AKT, p-mTOR and p-p70S6K. Bufalin inhibited tumor growth by inactivation of AKT/mTOR pathway.

4. Regulation of Wnt/β-Catenin by Bufalin

In the absence of Wnt signals, degradation of β-catenin is mediated by a destruction complex consisting of adenomatous polyposis coli (APC), Axin and glycogen synthase kinase-3 (GSK-3β) proteins. Following the binding of Wnt to receptors of Frizzled and LRP families on the cell surface, β-catenin efficiently moved into the nucleus and transcriptionally regulated a myriad of gene networks. Phosphorylation of GSK-3β at serine-9 resulted in the inactivation of GSK-3β. Therefore, GSK-3β inactivation led to activation and transportation of β-catenin to the nucleus [28][29][30][31]. In this section, the researchers highlight the recent breakthroughs that have been made in the field of molecular oncology and discuss how regulation of the Wnt/β-catenin pathway by bufalin will influence ongoing basic research and the design of rationale-based clinical trials to improve the treatment options for cancer patients.
Cell cycle-related kinase (CCRK) acted as an oncogenic master modulator for the activation and nuclear translocation of β-catenin, where it formed a complex with transcriptional factor TCF. Notably, the complex binds to promoter regions of EGFR (epidermal growth factor receptor) and CCND1 (cyclin D1). Bufalin efficiently reduced the levels of CCND1, EGFR, and CCRK. It was shown that CCRK overexpression promoted tumorigenesis by activation of β-catenin/TCF signaling. Subcutaneous inoculation of PLC5 cells into the right flanks of athymic nude mice was used for the construction of the xenograft rodent model. Tumor pieces were implanted into the liver lobes of nude mice for the development of orthotopic models. Bufalin not only reduced CCRK but also decreased nuclear levels of β-catenin in the tumor tissues [32].
Bufalin effectively blocked androgen receptor-mediated transcriptional upregulation of CCRK (cell cycle-related kinase) in HepG2.2.15 and PLC5 cells. Levels of phosphorylated androgen receptor were found to be reduced by bufalin. GSK-3β phosphorylation by CCRK caused activation of β-catenin. Bufalin inhibited HBx-mediated intrahepatic tumorigenicity, and reduced the levels of p-ARSer81, CCRK, p-GSK3βSer9, and active β-catenin in tumor tissues [33].
Bufalin markedly inhibited the migratory and invasive capacities of hepatocellular carcinoma cells, and efficiently caused reduction in the levels of p-GSK3βSer9 and active β-catenin in BEL-7402 cells [34].
Deregulated expression of β-catenin resulted in the instability of the complexes formed with E-cadherin. Dissociation of β-catenin and E-cadherin resulted in a loss of epithelial characteristics and potently promoted increasingly invasive phenotypes. Bufalin interfered with nuclear transportation of β-catenin in colorectal cancer cells [35].
The recent advancements in the characterization of aberrantly activated β-catenin target gene programming in cancer cells also provide exceptional prospects for pharmacological targeting of the oncogenic Wnt/β-catenin pathway. As illustrated by the examples given in this section, comprehensive experimental evaluation of the functional effects of bufalin on the Wnt/β-catenin pathway will be advantageous.

5. Regulation of TRAIL Pathway by Bufalin

Excitingly, a maze of information in the rapidly growing field of apoptosis research has unveiled dichotomously branched pathways, consisting of extrinsic and intrinsic apoptotic pathways. Binding of TRAIL to TRAIL-R1 or TRAIL-R2 results in oligomerization of receptors on the cell membrane and initiation of apoptotic cell death. Following ligand–receptor interactions, FAS associated protein with death domain (FADD) is recruited to death domain motifs within the carboxyl terminus of death receptors. Studies have shown that death inducible signaling complex (DISC) is formed at death receptors by assembly of multi-molecular machinery consisting of FADD and pro-caspase-8, and promotes the functionalization of caspase-8 [36][37][38][39][40][41]. During intrinsic apoptosis, loss of subcellular and submitochondrial compartmentalization triggered the exit of cytochrome c, SMAC/DIABLO, and OMI/HTRA. In this section, the researchers review collected key aspects associated with bufalin-mediated regulation of TRAIL-mediated apoptotic cell death.
Intriguingly, aggregations of lipid rafts as well as redistribution of death receptors (DR4, DR5) in lipid rafts were identified in bufalin-treated MCF-7 and MDA-MB-231 cancer cells. The findings revealed that lipid raft dysfunction caused resistance against TRAIL, whereas bufalin-mediated redistribution of DR4 and DR5 within lipid rafts significantly contributed to TRAIL-mediated apoptotic death in breast cancer cells. Depletion of cholesterol by methyl-β-cyclodextrin has been a widely used approach. Clustering of DR4 and DR5 was reduced markedly in cancer cells pre-treated with methyl-β-cyclodextrin [42].
Studies have yielded convincing evidence that Cbl-b negatively regulated the TRAIL-driven pathway. Cbl-b was downregulated by bufalin in MDA-MB-231 and MCF-7 cancer cells. Essentially, bufalin upregulated the levels of DR4 and DR5 by suppression in the levels of Cbl-b. Bufalin and TRAIL-mediated activation of ERK, JNK, and p38 MAPK was found to be significantly enhanced in Cbl-b-silenced cancer cells [43].
Bufalin increased the levels of Bax, cytochrome c, Endonuclease G and AIF (apoptosis-inducing factor). Concomitantly, bufalin reduced Bcl-2 in NPC-TW 076 cells. Additionally, bufalin stimulated the expression levels of TRAIL, DR4, DR5, and FADD [44].
The TRAIL pathway contains another protein that blocks caspase activation. Importantly, c-FLIP (cellular FLICE inhibitory protein) is an inactive homologue of caspase-8 that contains a DED but lacks a catalytically active site. Bufalin upregulated the expression of DR5 in T24 cancer cells. Moreover, TRAIL and bufalin efficiently reduced the levels of c-FLIP and XIAP in T24 cancer cells (Figure 3) [45].
Figure 3. Diagrammatic representation of regulation of TRAIL-mediated apoptotic death by bufalin. Importantly, bufalin enhanced the levels of FADD and DR4/DR5. Bufalin activated death inducible signaling complex. Bufalin triggered the release of cytochrome c and SMAC/DIABLO. C-FLIP prevented the formation of DISC but bufalin prominently reduced the levels of c-FLIP. Bufalin also inhibited Bcl-2 and XIAP.

6. Regulation of Non-Coding RNAs by Bufalin

More prominently, extraordinary strides have been made in the achievement of a high-resolution view of mechanistic regulation of cell signaling pathways by non-coding RNAs in different cancers. The widespread alteration of non-coding RNAs demonstrated that deregulation of miRNAs [46][47][48], lncRNAs [49][50][51][52], and circular RNAs [53][54][55] contributed to multiple hallmarks of cancer.

7. Tumor Inhibitory Role of Bufalin: Animal Model Studies

Osimertinib is a third-generation standard-of-care therapy for EGFR mutation-positive advanced non–small-cell lung cancers. Osimertinib caused considerable reduction in the levels of Mcl-1 in HCC827 and PC-9 cells. USP9X and Ku70 have been functionally characterized as Mcl-1 deubiquitinases. Studies had shown that deubiquitinases removed polyubiquitin chains from Mcl-1 and enhanced its stability (Figure 4). Levels of Mcl-1 levels were found to be robustly increased in Ku70-overexpressing PC-9 cells. However, silencing of Ku70 led to a notable reduction in the levels of Mcl-1 and enhanced osimertinib-sensitivity in PC-9/OR cells. Moreover, combinatorial treatment with osimertinib and bufalin significantly downregulated the levels of Ku70 and Mcl-1 in tumor tissues of NSCLC xenograft mouse models [56].
Figure 4. (A) Bufalin induced dissociation of KU70 and Mcl-1 and promoted degradation of Mcl-1. (B) Bufalin enhanced the interactions of ZFP91 and E2F2. Bufalin mediated an increase in the polyubiquitination levels of E2F2. (C) Bufalin inhibited calcineurin mediated dephosphorylation and nuclear accumulation of NFAT. NFAT stimulated the expression of c-Myc. (D,E) Bufalin enhanced the expression of NKG2D in natural killer cells. Bufalin reduced the levels of ADAM9 and inhibited the shedding of MICA.

8. Regulation of Tumor Microenvironment by Bufalin

Macrophages have functional plasticity and can be polarized into two characteristically distinct phenotypes for modulation of the tumor microenvironment.
Bufalin induced the activation the NF-κB pathway and triggered upregulation of IFNγ and TNFα. However, constitutive overexpression of p50 in bone-marrow-derived macrophage (BMDMs) markedly counteracted the effects of bufalin and concomitantly reduced the expression of M1-associated genes. Importantly, the proportions of CD163+CD206+ M2 macrophages were found to be sharply increased and caused reversal of the pre-dominant effects of bufalin-primed M1 macrophages. In HCC-bearing animal models, overexpression of p50 led to remarkable impairment in the tumor-inhibitory effects of bufalin. Furthermore, the percentage of tumor-promoting M2 macrophages was found to be enhanced in mice bearing p50-overexpressing tumors. The accumulation of bufalin-induced CD4+ and CD8+ T cells in the tissue microenvironment was also reduced in mice inoculated with p50-overexpressing cancer cells [57].
Bufalin efficiently inhibited chemo-resistant cell-mediated polarization of M2 macrophages. Macrophage migration inhibitory factor (MIF) inhibited the polarization of macrophages. Bufalin blocked SRC-3-mediated transcriptional upregulation of MIF and abrogated macrophage polarization [58].
First discovered in the late 1990s, activating receptor NKG2D participates in the immunosurveillance of cytotoxic lymphocytes primarily through identification of stress-induced ligands MICA/B on the surfaces of cancer cells. Bufalin upregulated membrane bound-MICA (m-MICA) in liver cancer cells and reduced the levels of soluble s-MICA. Bufalin enhanced the expression of NKG2D in NK-92MI cells. Moreover, expression levels of inhibitory receptors (NKG2A, TIGIT and CTLA-4) were also found to be suppressed in NK-92MI cells. Bufalin reduced the levels of ADAM9 and inhibited the shedding of MICA (Figure 4) [59].

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Subjects: Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Ammad Ahmad Farooqi
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Venera S. Rakhmetova
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Gulnara Kapanova
,
Gulnara Tashenova
,
Aigul Tulebayeva
,
Aida Akhenbekova
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Onlassyn Ibekenov
,
Assiya Turgambayeva
,
Baojun Xu
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Update Date: 24 Mar 2023
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