Bufalin-Mediated Regulation of Cell Signaling Pathways in Different Cancers: Spotlight on JAK/STAT, Wnt/β-Catenin, mTOR, TRAIL/TRAIL-R, and Non-Coding RNAs

Abstract

The renaissance of research into natural products has unequivocally and paradigmatically shifted our knowledge about the significant role of natural products in cancer chemoprevention. 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. Bufalin-related clinical studies are insufficient and interdisciplinary researchers require detailed analysis of the existing knowledge gaps.

Keywords: apoptosis; bufalin; cancer; cell signaling; metastasis.

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.

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.

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.

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.