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The Notch Signaling Pathway as a Mediator of Tumor Survival.

作者：Capaccione KM, Pine SR.

The Notch signaling pathway is evolutionarily conserved and responsible for cell fate determination in the developing embryo and mature tissue. At the molecular level, ligand binding activates Notch signaling by liberating the Notch intracellular domain, which then translocates into the nucleus and activates gene transcription. Despite the elegant simplicity of this pathway, which lacks secondary messengers or a signaling cascade, Notch regulates gene expression in a highly context- and cell-type-dependent manner. Notch signaling is frequently dysregulated, most commonly by overactivation, across many cancers and confers a survival advantages on tumors, leading to poorer outcomes for patients. Recent studies demonstrate how Notch signaling increases tumor cell proliferation, and provide evidence that active Notch signaling maintains the cancer stem cell pool, induces epithelial-mesenchymal transition, and promotes chemoresistance. These studies imply that pharmacological inhibition of Notch signaling may refine control of cancer therapy and improve patient survival. Gamma-secretase inhibitors are drugs that inhibit Notch signaling and may be successful in controlling cancer cell growth in conjunction with standard chemotherapy, but substantial side effects have hampered their widespread use. Recent efforts have been aimed at the development of antibodies against specific Notch receptors and ligands with the hope of limiting side effects while providing the same therapeutic benefit as gamma-secretase inhibitors. Together, studies characterizing Notch signaling and modulation have offered hope that refined methods targeting Notch may become powerful tools in anti-cancer therapeutics.

Lef1 contributes to the differentiation of bulge stem cells by nuclear translocation and cross-talk with the notch signaling pathway.

作者：Zhang Y, Yu J, Shi C, Huang Y, Wang Y, Yang T, Yang J.

Lymphoid enhancer binding factor-1 (Lef1) is an essential regulatory protein in the Wnt signal pathway, which controls cell growth and differentiation. Investigators in the field of skin biology have confirmed that multipotent bulge stem cells (BSCs) are responsible for hair follicle development and regeneration. However, the role of Lef1 remains poorly understood. In this study, we investigated the pattern of Lef1 expression at different stages of the hair growth cycle. Lef1 was strongly expressed during anagen but attenuated in both catagen- and telogen-phase hair follicles in vivo. When stem cells were induced to differentiate toward a hair fate in a co-culture system, Lef1 was notably up-regulated and accumulated in the nucleus, appearing to activate the target protein c-myc and jagged1. Simultaneously, the Wnt and Notch signaling pathways were co-activated, as confirmed by the increased expression of β-catenin and notch1. Plasmids expressing Lef1 and ΔNLef1, a construct in which the β-catenin-binding domain of Lef1 was deleted, were used to evaluate the effects of Lef1 on stem cell differentiation. Lef1 overexpression promoted bulge stem cell differentiation toward a hair fate, which was accompanied by the subsequent migration of β-catenin into the nucleus, whereas no changes were observed in the control group. Taken together, our results demonstrate that Lef1 plays an important role in bulge stem cell differentiation, promoting β-catenin translocation into the nucleus, activating downstream signaling molecules, eventually causing hair follicle bulge stem cells to adopt the hair fate.

Wnt signaling pathway in rheumatoid arthritis, with special emphasis on the different roles in synovial inflammation and bone remodeling.

作者：Miao CG, Yang YY, He X, Li XF, Huang C, Huang Y, Zhang L, Lv XW, Jin Y, Li J.

Rheumatoid arthritis (RA) is a chronic symmetrical autoimmune disease of unknown etiology that affects primarily the diarthrodial joints. Characteristic features of RA pathogenesis are synovial inflammation and proliferation accompanied by cartilage erosion and bone loss. Fibroblast-like synoviocytes (FLS) display an important role in the pathogenesis of RA. Several lines of evidence show that the Wnt signaling pathway significantly participates in the RA pathogenesis. The Wnt proteins are glycoproteins that bind to the Fz receptors on the cell surface, which leads to several important biological functions, such as cell differentiation, embryonic development, limb development and joint formation. Accumulated evidence has suggested that this signaling pathway plays a key role in the FLS activation, bone resorption and joint destruction during RA development. Greater knowledge of the role of the Wnt signaling pathway in RA could improve understanding of the RA pathogenesis and the differences in RA clinical presentation and prognosis. In this review, new advances of the Wnt signaling pathway in RA pathogenesis are discussed, with special emphasis on its different roles in synovial inflammation and bone remodeling. Further studies are needed to reveal the important role of the members of the Wnt signaling pathway in the RA pathogenesis and treatment.

Rspo 1 promotes osteoblast differentiation via Wnt signaling pathway.

作者：Sharma AR, Choi BS, Park JM, Lee DH, Lee JE, Kim HS, Yoon JK, Song DK, Nam JS, Lee SS.

R-spondin (Rspo)s proteins are a new group of Wnt/beta-catenin signaling agonists. These signaling molecules are known to be involved in the developmental stages of skeletal system. Recent studies in various murine osteoblast models have proposed that Rspo 1 may interact with Wnt signaling pathway to induce differentiation in osteoblasts. Though findings in murine osteoblasts implicate a synergestic role of Rspo 1 with Wnt signaling, still no study has addressed the similar role in more clinically applicable osteoblast models i.e., human cell lines or primary cells. Therefore, in the present study, we investigated the possible role of Rspo 1 during differentiation process of human in vitro osteoblast cell models like primary osteoblasts or human osteoprogenitor cell line hFOB 1.19 along with murine preosteoblast cell line MC3T3 E-1. Our results showed increase in Rspo 1 at transcript level during differentiating phase of human primary osteoblasts and human FOB 1.19 cells. We also found that Rspo 1 (100 ng/mL) acts additively with Wnt3a to activate Wnt signaling, as confirmed by luciferase activity after transfection of TOPFLASH construct to hFOB 1.19 cells. Similar additive role of Rspo 1 and Wnt3a was apparent in alkaline phosphatase (ALP) activity analysis of human primary cells. Moreover, a reduction in ALP activity was observed with knock-down of Rspo 1 by transfected shRNA in hFOB 1.19 cells. These results suggested the possibility of autocrine regulation by Rspo 1 on the osteogenic activities in human in vitro osteoblast models. Furthermore, these results were corroborated in MC3T3-E1, murine osteoblast cell model. Osteoblastic differentiation was induced by transfection of Rspo 1 which was confirmed by increased ALP staining and qRT-PCR analysis of osteogenic markers, such as Runx2 and osteocalcin. In conclusion, present study highlights the role of Rspo 1 in bone remodeling where it activates Wnt signaling to induce differentiation, as shown in human as well murine in vitro osteoblast cell models.

Curcumin reverses the epithelial-mesenchymal transition of pancreatic cancer cells by inhibiting the Hedgehog signaling pathway.

作者：Sun XD, Liu XE, Huang DS.

Curcumin, a phenolic compound extracted from Zingiberaceae turmeric, has strong anti-inflammatory, antioxidant and antitumor properties. However, the anticarcinogenic mechanism of curcumin has yet to be fully elucidated. Epithelial-mesenchymal transition (EMT) induced by transforming growth factor-β1 (TGF-β1) is involved in the promotion of tumor invasion and metastasis, and is closely related to the drug resistance of tumor cells. The abnormal activation of Hedgehog signaling also plays an important role in tumorigenesis and metastasis. In order to investigate whether curcumin can reverse the TGF-β1-stimulated EMT of pancreatic cancer PANC-1 cells, and its possible mechanism, the pancreatic cancer cell line PANC-1 was stimulated with TGF-β1 (5 ng/ml) for 7 days to induce formation of EMT, and the TGF-β1-stimulated PANC-1 cells were treated with different concentrations of curcumin (10, 20 and 30 μmol/ml) for 48 h. The growth inhibition rate of the cells was measured by MTT assay, apoptosis was detected by flow cytometry, the expression levels of Shh, GLI1, E-cadherin and vimentin were detected by western blot analysis, and cell invasion and migration ability were examined by transwell cell invasion assay and wound healing assay. Following stimulation with TGF-β1, the expression levels of Shh, GLI1 and vimentin in the TGF-β1-stimulated group were significantly increased, compared with those in the control group (P<0.01, respectively). The expression levels of E-cadherin in the TGF-β1-stimulated group were significantly decreased, compared with those in the control group (P<0.01). The TGF-β1-stimulated PANC-1 cells were treated with curcumin and the results showed that curcumin significantly inhibited TGF-β1-stimulated PANC-1 cell proliferation and induced apoptosis, compared with other groups (P<0.01), and the expression levels of Shh, GLI1 and vimentin in the curcumin-treated group were significantly decreased compared with those in the control group (P<0.01, respectively). The expression level of E-cadherin in the curcumin-treated group was significantly increased compared with that in the control group (P<0.01). Cell invasion in the curcumin-treated group (30 μmol/ml) was significantly decreased compared with that in the control group (P<0.01). The scratch wounds in the curcumin-treated group healed slower compared with those in the control group (P<0.01). Curcumin significantly inhibited the invasion and migration of TGF-β1-stimulated PANC-1 cells. These results indicate that curcumin can inhibit the proliferation of TGF-β1-stimulated PANC-1 cells, it can induce apoptosis, and reverse the EMT. The possible underlying molecular mechanisms are through inhibition of the Shh-GLI1 signaling pathway.

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Hedgehog Signaling Pathway and Cancer Therapeutics: Progress to Date.

作者：Ruch JM, Kim EJ.

The Hedgehog (Hh) pathway is a developmental signaling pathway involved in numerous developmental processes, including determination of cell fate, patterning, proliferation, survival, and differentiation. While this pathway is silenced in most adult tissues, aberrant activation of it has been documented in a variety of malignancies. In cancers such as basal cell carcinoma (BCC), ligand-independent mechanisms lead to constitutive Hh pathway activation through mutations in components of the pathway, including patched-1 (PTCH1) or smoothened (SMO). On the contrary, numerous other solid and hematologic tumors have been shown to harbor ligand-dependent activation of the Hh pathway by autocrine or paracrine mechanisms. Given that aberrant Hh pathway signaling has been seen in a number of malignancies, this pathway has been an attractive target for drug development. While the best-characterized approach is to target the SMO receptor, other rational approaches for inhibiting the Hh pathway include inhibiting downstream components or directly binding Hh ligands. In January of 2012, vismodegib, a SMO antagonist, became the first agent to target the Hh pathway to receive approval by the United States Food and Drug Administration (FDA) after this agent showed remarkable activity in phase I and II trials for the treatment of BCC. Despite promising preclinical studies with Hh pathway inhibitors in other malignancies that have suggested a potential role for these agents, attempts to translate this potential to clinical benefit has been disappointing. Future efforts will require further careful interpretation and analysis to determine the potential determinants and predictors of efficacy. Currently, several phase I and II trials evaluating Hh inhibitors in a variety of tumor settings are underway.

Characterization of a novel curcumin analog P1 as potent inhibitor of the NF-κB signaling pathway with distinct mechanisms.

作者：Peng YM, Zheng JB, Zhou YB, Li J.

Aim:Curcumin has shown promising anticancer activity, which relies on its inhibition on NF-κB pathway. In this study, we characterized the pharmacological profile of a novel curcumin analog P1 and elucidate the related mechanisms.Methods:HEK293/NF-κB cells, stably transfected with an NF-κB-responsive luciferase reporter plasmid, were generated for high-throughput screen (HTS). Eight cancer cell lines, including PC3, COLO 205, HeLa cells etc. were tested. Cell viability was assessed using the sulforhodamine B (SRB) assays. Cell apoptosis was evaluated using FACS, immunocytochemistry, and Western blotting. H2-DCFDA and MitoSOX Red were used to detect cellular and mitochondrial reactive oxygen species (ROS). The mitochondrial function was evaluated using mitochondrial oxygen consumption assay.Results:P1, a tropinone curcumin, was found in HTS targeting the NF-κB pathway. Its IC50 value in inhibition of TNF-α-induced NF-κB activation was 0.8 μmol/L, whereas its IC50 values in inhibiting the growth of A549 and HeLa cells were 1.24 and 0.69 μmol/L, respectively, which was 20- to 30-fold more potent than curcumin. The inhibition of P1 on the NF-κB pathway was further addressed in HeLa cells: The compound up to 10 μmol/L did not affect the binding of NF-κB to DNA, but markedly inhibited NF-κB nuclear translocation, IκB degradation and IκB kinase phosphorylation. The compound (1 and 3 μmol/L) concentration-dependently induced ROS generation, whereas curcumin up to 20 μmol/L had no effect. P1-induced ROS generation was mainly localized in mitochondria, and reversed by NAC. Moreover, the compound significantly enhanced TNF-α-induced apoptosis.Conclusion:P1 is a novel curcumin analog with potent anticancer activities, which exerts a distinct inhibition on the NF-κB pathway.

Sulforaphane controls TPA-induced MMP-9 expression through the NF-κB signaling pathway, but not AP-1, in MCF-7 breast cancer cells.

作者：Lee YR, Noh EM, Han JH, Kim JM, Hwang BM, Kim BS, Lee SH, Jung SH, Youn HJ, Chung EY, Kim JS.

Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)-butane] is an isothiocyanate found in some cruciferous vegetables, especially broccoli. Sulforaphane has been shown to display anti-cancer properties against various cancer cell lines. Matrix metalloproteinase-9 (MMP-9), which degrades the extracellular matrix (ECM), plays an important role in cancer cell invasion. In this study, we investigated the effect of sulforaphane on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced MMP-9 expression and cell invasion in MCF-7 cells. TPA-induced MMP-9 expression and cell invasion were decreased by sulforaphane treatment. TPA substantially increased NF-κB and AP-1 DNA binding activity. Pre-treatment with sulforaphane inhibited TPA-stimulated NF-κB binding activity, but not AP-1 binding activity. In addition, we found that sulforaphane suppressed NF-κB activation, by inhibiting phosphorylation of IκB in TPA-treated MCF-7 cells. In this study, we demonstrated that the inhibition of TPA-induced MMP-9 expression and cell invasion by sulforaphane was mediated by the suppression of the NF-κB pathway in MCF-7 cells. [BMB Reports 2013; 46(4): 201-206].

Suppression of inhibitory GABAergic transmission by cAMP signaling pathway: alterations in learning and memory mutants.

作者：Ganguly A, Lee D.

The cAMP signaling pathway mediates synaptic plasticity and is essential for memory formation in both vertebrates and invertebrates. In the fruit fly Drosophila melanogaster, mutations in the cAMP pathway lead to impaired olfactory learning. These mutant genes are preferentially expressed in the mushroom