Deguelin‐induced blockade of PI3K/protein kinase B/MAP kinase signaling in zebrafish and breast cancer cell lines is mediated by down‐regulation of fibroblast growth factor receptor 4 activity

Abstract

Deguelin, a natural component derived from leguminous plants, has been used as pesticide in some regions. Accumulating evidence show that deguelin has promising chemopreventive and therapeutic activities against cancer cells. This study shows that low concentrations of deguelin can lead to significant delay in zebrafish embryonic development through growth inhibition and induction of apoptosis. Furthermore, we identified fibroblast growth factor receptor 4 (FGFR4) as the putative target of deguelin. The candidate was initially identified by a microarray approach and then validated through in vitro experiments using hormone‐responsive (MCF‐7) and nonresponsive (MDA‐MB‐231) human breast cancer cell lines. The results show that deguelin suppressed cell proliferation and induced apoptosis in both cancer cell lines, but not in Hs 578Bst cells, by blocking PI3K/AKT and mitogen‐activated protein kinases (MAPK) signaling. The FGFR4 mRNA and protein level also diminished in a dose‐dependent manner. Interestingly, we found that forced FGFR4 overexpression attenuated deguelin‐induced proliferative suppression and apoptotic cell death in both zebrafish and MCF‐7 cell lines, p‐AKT and p‐ERK levels were restored upon FGFR4 overexpression. Taken together, our results strongly suggest that deguelin inhibition of PI3K/AKT and MAPK signaling in zebrafish and breast cancer cell lines is partially mediated through down‐regulation of FGFR4 activity.

Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain

“…Particularly over the past 2 decades, there has been a considerable focus on studying deguelin as a chemopreventative, since the discovery of its antiproliferative properties on cells (70). These properties have been attributed to the modulation of myriad molecular pathways in various cancer cell types (6,13,17,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33), and the question arose as to whether deguelin might also have antiparasitic effects.…”

“…It is not clear whether the transcriptional down-regulation of these genes is a direct or indirect response to deguelin exposure and should be a subject for additional investigation. Finally, of interest was the suppression of genes that are involved in the PI3K-Akt kinase signaling pathway (represented by 14 genes), which has been identified as a target of deguelin in mammalian cells (24)(25)(26). Recently, this pathway was shown to modulate oxygen metabolism via phosphorylation of pyruvate dehydrogenase (103).…”

Deguelin inhibits epithelial‐to‐mesenchymal transition and metastasis of human non‐small cell lung cancer cells by regulating NIMA‐related kinase 2

“…It has been reported that NEK2 played an important role in inducing metastasis and drug resistance in hepatoma cells by activating the phosphorylated protein kinase B/nuclear factor‐κB signaling pathway and MMPs. Other reports have suggested that NEK2 overexpression induced the activation of the phosphoinositide 3‐kinase/protein kinase B signaling pathway and increased β‐catenin protein expression and β‐catenin relocalization in colorectal cancer . In our study, we investigated the role of NEK2 in NSCLC and found that NEK2 silencing could inhibit the migration and invasion of NSCLC cells.…”

TGF-β1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression

“…We used various inhibitors against ERK, JNK and p38 MAPKs, and TGF-β1 induced FGFR4 expression via the ERK pathway in HCC. Previous studies reported that changes in FGFR4 expression may activate ERK pathways in lung cancer [29], prostate cancer [30], and studies show that low expression of FGFR4 may cause reduced ERK pathway signaling in breast cancer [31]. Thus, crosstalk among TGF-β1, FGFR4 and the ERK pathway requires more study.…”