Fibroblast Growth Factor-2 Suppresses Oridonin-Induced L929 Apoptosis Through Extracellular Signal-Regulated Kinase-Dependent and Phosphatidylinositol 3-Kinase-Independent Pathway

Huang, Jian; Li-jun, WU; Tashiro, Shin‐ichi; Onodera, Satoshi; Ikejima, Takashi

doi:10.1254/jphs.fpj06004x

Cited by 16 publications

(12 citation statements)

References 40 publications

(19 reference statements)

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“…In the present study, protein components and their anti-tumor activity of fresh toad venom (FTV) were compared with those of dried toad venom (DTV). Furthermore, basic fibroblast growth factor (bFGF), one of the growth factors involved in angiogenesis in cancer metastasis (24–26), was selected as a biomarker for cancers to investigate protein components from toad venom. A bFGF-immobilized affinity column was used to capture active components that can interact with bFGF.…”

Section: Introductionmentioning

confidence: 99%

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Identification of anti-tumor components from toad venom

Gao

Wang

et al. 2017

Oncology Letters

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Secretion of granular glands from the skin of amphibians is a fascinating resource of active substances, particularly for cancer therapy in clinical practice of Traditional Chinese Medicine. A variety of anti-tumor peptides have been isolated from different toads and frogs; however, no anti-tumor peptides are reported in toad venom of Bufo gargarizans. Firstly, soluble fraction from fresh toad venom (FTV) was compared with that from dried toad venom (DTV), using HPLC analysis. It was revealed that FTV has a different HPLC chromatography compared with DTV. Soluble fraction of FTV is more toxic to SH-SY5Y cells than that of DTV, as evaluated by MTT assay. Secondly, it was identified that protein components from soluble fractions of FTV and DTV possess different patterns by SDS-PAGE analysis, and proteins from FTV are also more toxic than that from DTV. Thirdly, an immobilized basic fibroblast growth factor (bFGF) affinity column was used to isolate bFGF-binding components from soluble fraction of FTV, and it was identified that bFGF-binding components prohibited bFGF-dependent neurite growth of SH-SY5Y cells. Finally, it was identified that bFGF-binding components activated apoptosis via upregulation of caspase-3 and caspase-8 expression in SH-SY5Y cells. These data suggest that FTV contains active components that interact with bFGF and activate apoptosis in SH-SY5Y cells.

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Section: Introductionmentioning

confidence: 99%

“…A bFGF-immobilized affinity column was used to capture active components that can interact with bFGF. The bFGF can inhibit the apoptosis induced by oridonin in L929 tumor cells (26), and cause tumor migration by regulating several pathways (27,28). The mechanism of anti-tumor activity of active components was preliminarily studied.…”

Section: Introductionmentioning

confidence: 99%

Identification of anti-tumor components from toad venom

Gao

Wang

et al. 2017

Oncology Letters

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“…Signaling by FGF2 has been shown to be important for inhibition of apoptosis through PI3K/AKT and IKKβ [11], [12], and FGF signaling has also been shown to decrease TNFα-induced apoptosis through activation of the p44/42 MAPK pathway [13]. Regulatory interactions between FGFR4 and NFκB signaling pathways have not previously been reported, although both pathways represent major axes of cell signaling.…”

Section: Introductionmentioning

confidence: 99%

The Receptor Tyrosine Kinase FGFR4 Negatively Regulates NF-kappaB Signaling

et al. 2010

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BackgroundNFκB signaling is of paramount importance in the regulation of apoptosis, proliferation, and inflammatory responses during human development and homeostasis, as well as in many human cancers. Receptor Tyrosine Kinases (RTKs), including the Fibroblast Growth Factor Receptors (FGFRs) are also important in development and disease. However, a direct relationship between growth factor signaling pathways and NFκB activation has not been previously described, although FGFs have been known to antagonize TNFα-induced apoptosis.Methodology/Principal FindingsHere, we demonstrate an interaction between FGFR4 and IKKβ (Inhibitor of NFκB Kinase β subunit), an essential component in the NFκB pathway. This novel interaction was identified utilizing a yeast two-hybrid screen [1] and confirmed by coimmunoprecipitation and mass spectrometry analysis. We demonstrate tyrosine phosphorylation of IKKβ in the presence of activated FGFR4, but not kinase-dead FGFR4. Following stimulation by TNFα (Tumor Necrosis Factor α) to activate NFκB pathways, FGFR4 activation results in significant inhibition of NFκB signaling as measured by decreased nuclear NFκB localization, by reduced NFκB transcriptional activation in electophoretic mobility shift assays, and by inhibition of IKKβ kinase activity towards the substrate GST-IκBα in in vitro assays. FGF19 stimulation of endogenous FGFR4 in TNFα-treated DU145 prostate cancer cells also leads to a decrease in IKKβ activity, concomitant reduction in NFκB nuclear localization, and reduced apoptosis. Microarray analysis demonstrates that FGF19 + TNFα treatment of DU145 cells, in comparison with TNFα alone, favors proliferative genes while downregulating genes involved in apoptotic responses and NFκB signaling.Conclusions/SignificanceThese results identify a compelling link between FGFR4 signaling and the NFκB pathway, and reveal that FGFR4 activation leads to a negative effect on NFκB signaling including an inhibitory effect on proapoptotic signaling. We anticipate that this interaction between an RTK and a component of NFκB signaling will not be limited to FGFR4 alone.

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“…Activated ERK decreases the ratio of Bcl‐2/Bax by mediating phosphorylation of Bcl‐2. Inhibition of Bcl‐2, presence of FGF‐2 and initiation of Ras/Raf/ERK signalling, were involved in protection against oridon‐induced apoptosis (Fig. ).…”

Section: Oridonin‐induced Apoptosis Pathways In Cancermentioning

confidence: 95%

Oridonin: targeting programmed cell death pathways as an anti‐tumour agent

Liu¹,

Ouyang

Peng

et al. 2012

Cell Proliferation

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Oridonin, an active diterpenoid isolated from traditional Chinese herbal medicine, has drawn rising attention for its remarkable apoptosis- and autophagy-inducing activity and relevant molecular mechanisms in cancer therapy. Apoptosis is a well known type of cell death, whereas autophagy can play either pro-survival or pro-death roles in cancer cells. Accumulating evidence has recently revealed relationships between apoptosis and autophagy induced by oridonin; however, molecular mechanisms behind them remain to be discovered. In this review, we focus on highlighting updated research on oridonin-induced cell death signalling pathways implicated in apoptosis and autophagy, in many types of cancer. In addition, we further discuss cross-talk between apoptosis and autophagy induced by oridonin, in cancer. Taken together, these findings open new perspectives for further exploring oridonin as a potential anti-tumour agent targeting apoptosis and autophagy, in future anti-cancer therapeutics.

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Fibroblast Growth Factor-2 Suppresses Oridonin-Induced L929 Apoptosis Through Extracellular Signal-Regulated Kinase-Dependent and Phosphatidylinositol 3-Kinase-Independent Pathway

Cited by 16 publications

References 40 publications

Identification of anti-tumor components from toad venom

Identification of anti-tumor components from toad venom

The Receptor Tyrosine Kinase FGFR4 Negatively Regulates NF-kappaB Signaling

Oridonin: targeting programmed cell death pathways as an anti‐tumour agent

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