6-Bromoindirubin-3’-oxime promotes osteogenic differentiation of canine BMSCs through inhibition of GSK3β activity and activation of the Wnt/β-catenin signaling pathway

Zhao, Xiaoe; Yang, Zeng-Ming; Gao, Zhen; Ge, Junbang; Wei, Qiang; Ma, Baohua

doi:10.1590/0001-3765201920180459

Cited by 14 publications

(18 citation statements)

References 41 publications

(23 reference statements)

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“…In contrast, LEF1 was shown to be overexpressed in the initial and later phases of bone repair [17]. The activated Wnt/β-catenin pathway can promote the osteogenic differentiation of BMSCs [18]. Although the activation of the Wnt/β-catenin pathway results in bone formation, increased bone mass results from excessive bone formation rather than bone resorption in both situations [19].…”

Section: Introductionmentioning

confidence: 99%

The osteogenic differentiation of human adipose-derived stem cells is regulated through the let-7i-3p/LEF1/β-catenin axis under cyclic strain

Luo

et al. 2019

Stem Cell Res Ther

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Background: The Wnt/β-catenin pathway is involved in the osteogenic differentiation of human adipose-derived stem cells (hASCs) under cyclic strain. Very little is known about the role of microRNAs in these events. Methods: Cells were obtained using enzyme digestion methods, and proliferation was detected using Cell Counting Kit 8. Cell cycles and immunophenotypes were detected by flow cytometry. The multilineage potential of hASCs was induced by induction media. Cyclic strain was applied to hASCs (0.5 Hz, 2 h/day, 6 days) to induce osteogenic differentiation and miRNA changes. Bioinformatic and dual-luciferase analyses confirmed lymphoid enhancer factor 1 (LEF1) as a potential target of let-7i-3p. The effect of let-7i-3p on LEF1 in hASCs transfected with a let-7i-3p mimic and inhibitor was analyzed by immunofluorescence. hASCs were transfected with a let-7i-3p mimic, inhibitor, or small interfering RNA (siRNA) against LEF1 and β-catenin. Quantitative real-time PCR (qPCR) and western blotting were performed to examine the osteogenic markers and Wnt/β-catenin pathway at the mRNA and protein levels, respectively. Immunofluorescence and western blotting were performed to confirm the activation of the Wnt/β-catenin pathway. Results: Flow cytometry showed that 82.12% ± 5.83% of the cells were in G1 phase and 17.88% ± 2.59% of the cells were in S/G2 phase; hASCs were positive for CD29, CD90, and CD105. hASCs could have the potential for osteogenic, chondrogenic, and adipogenic differentiation. MicroRNA screening via microarray showed that let-7i-3p expression was decreased under cyclic strain. Bioinformatic and dual-luciferase analyses confirmed that LEF1 in the Wnt/β-catenin pathway was the target of let-7i-3p. Under cyclic strain, the osteogenic differentiation of hASCs was promoted by overexpression of LEF1and β-catenin and inhibited by overexpression of let-7i-3p. hASCs were transfected with let-7i-3p mimics and inhibitor. Gain-or loss-of-function analyses of let-7i-3p showed that the osteogenic differentiation of hASCs was promoted by decreased let-7i-3p expression and inhibited by increased let-7i-3p expression. Furthermore, high LEF1 expression inactivated the Wnt/β-catenin pathway in let-7i-3p-enhanced hASCs. In contrast, let-7i-3p inhibition activated the Wnt/β-catenin pathway. Conclusions: Let-7i-3p, acting as a negative regulator of the Wnt/β-catenin pathway by targeting LEF1, inhibits the osteogenic differentiation of hASCs under cyclic strain in vitro.

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Section: Introductionmentioning

confidence: 99%

The osteogenic differentiation of human adipose-derived stem cells is regulated through the let-7i-3p/LEF1/β-catenin axis under cyclic strain

Luo

et al. 2019

Stem Cell Res Ther

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“…However, as observed for osteogenesis, the simultaneous use of inhibitors and C 2 S NPs could improve the effect of the inhibitor on the expression level of β-catenin. This phenomenon might be related to our observation that C 2 S NPs could be taken into the nucleus by cells, followed by direct activation of the transcription factor β-catenin and mediation of BMSC osteogenic differentiation [ 39 ]. Simultaneously, we also found that the expression of ULK1 was upregulated in vivo.…”

Section: Discussionmentioning

confidence: 95%

“…Studies have found that AMPK can directly or indirectly inhibit mTOR activation of the ULK1 pathway, while the Wnt/β-catenin pathway has been found to be related to osteogenic differentiation. We speculated that C 2 S NPs could activate autophagy through activation of the AMPK/ULK1 pathway and then activate the Wnt/β-catenin pathway to promote osteogenesis [ 39 ]. We verified the expression of related proteins in this pathway by Western blotting after coculture of C 2 S NPs and BMSCs.…”

Section: Discussionmentioning

confidence: 99%

The mTOR/ULK1 signaling pathway mediates the autophagy-promoting and osteogenic effects of dicalcium silicate nanoparticles

2020

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A novel bioactive inorganic material containing silicon, calcium and oxygen, calcium silicate (Ca 2 SiO 4 , C 2 S) with a CaO-SiO 2 ingredient, has been identified as a potential candidate for artificial bone. Autophagy has an essential function in adult tissue homoeostasis and tumorigenesis. However, little is known about whether silicate nanoparticles (C 2 S NPs) promote osteoblastic differentiation by inducing autophagy. Here we investigated the effects of C 2 S NPs on bone marrow mesenchymal stem cell differentiation (BMSCs) in osteoblasts. Furthermore, we identified the osteogenic gene and protein expression in BMSCs treated with C 2 S NPs. We found that autophagy is important for the ability of C 2 S NPs to induce osteoblastic differentiation of BMSCs. Our results showed that treatment with C 2 S NPs upregulated the expression of BMP2, UNX2, and OSX in BMSCs, and significantly promoted the expression of LC3 and Beclin, while P62 (an autophagy substrate) was downregulated. C 2 S NP treatment could also enhance Alizarin red S dye (ARS), although alkaline phosphatase (ALP) activity was not significantly changed. However, all these effects could be partially reversed by 3-MA. We then detected potential signaling pathways involved in this biological effect and found that C 2 S NPs could activate autophagy by suppressing mTOR and facilitating ULK1 expression. Autophagy further activated β-catenin expression and promoted osteogenic differentiation. In conclusion, C 2 S NPs promote bone formation and osteogenic differentiation in BMSCs by activating autophagy. They achieve this effect by activating mTOR/ ULK1, inducing autophagy, and subsequently triggering the WNT/β-catenin pathway to boost the differentiation and biomineralization of osteoblasts.

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“…We used a Wnt signaling activator (6-bromoindirubin-3ˊ -oxime (BIO) ( Zhao et al, 2019 ) and pcDNA3-cMyc ( Ricci et al, 2004 ) to enhance c-Myc expression in OACM5.1C cells which showed lowest c-Myc expression in our panel of EC cell lines tested. BIO is a novel small molecule inhibitor of glycogen synthase kinase 3 beta (GSK3β) and activator of the wnt/β-catenin pathway ( Zhao et al, 2019 ). Activation of the wnt/β-catenin pathway can upregulate c-Myc expression in various cells ( Li et al, 2012 ; Zhang et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we have demonstrated the efficacy C-Myc expression was manipulated pharmacologically and genetically. We used a Wnt signaling activator (6bromoindirubin-3ˊ-oxime (BIO) (Zhao et al, 2019) and pcDNA3-cMyc (Ricci et al, 2004) to enhance c-Myc expression in OACM5.1C cells which showed lowest c-Myc expression in our panel of EC cell lines tested. BIO is a novel small molecule inhibitor of glycogen synthase kinase 3 beta (GSK3β) and activator of the wnt/β-catenin pathway (Zhao et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer

et al. 2021

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Tumors with elevated c-Myc expression often exhibit a highly aggressive phenotype, and c-Myc amplification has been shown to be frequent in esophageal cancer. Emerging data suggests that synthetic lethal interactions between c-Myc pathway activation and small molecules inhibition involved in cell cycle signaling can be therapeutically exploited to preferentially kill tumor cells. We therefore investigated whether exploiting elevated c-Myc expression is effective in treating esophageal cancer with the CDK inhibitor flavopiridol. We found frequent overexpression of c-Myc in human esophageal cancer cell lines and tissues. c-Myc overexpression correlated with accelerated esophageal cancer subcutaneous xenograft tumor growth. Esophageal cancer cells with elevated c-Myc expression were found preferentially more sensitive to induction of apoptosis by the CDK inhibition flavopiridol compared to esophageal cancer cells with lower c-Myc expression. In addition, we observed that flavopiridol alone or in combination with the chemotherapeutic agent nanoparticle albumin-bound paclitaxel (NPT) or in combinations with the targeted agent BMS-754807 significantly inhibited esophageal cancer cell proliferation and subcutaneous xenograft tumor growth while significantly enhancing overall mice survival. These results indicate that aggressive esophageal cancer cells with elevated c-Myc expression are sensitive to the CDK inhibitor flavopiridol, and that flavopiridol alone or in combination can be a potential therapy for c-Myc overexpressing esophageal cancer.

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6-Bromoindirubin-3’-oxime promotes osteogenic differentiation of canine BMSCs through inhibition of GSK3β activity and activation of the Wnt/β-catenin signaling pathway

Abstract: Bromoindirubin-3'-oxime promotes osteogenic differentiation of canine BMSCs through inhibition of GSK3β activity and activation of the Wnt/β-catenin signaling pathway. An Acad Bras Cienc 91: e20180459.

Cited by 14 publications

References 41 publications

The osteogenic differentiation of human adipose-derived stem cells is regulated through the let-7i-3p/LEF1/β-catenin axis under cyclic strain

The osteogenic differentiation of human adipose-derived stem cells is regulated through the let-7i-3p/LEF1/β-catenin axis under cyclic strain

The mTOR/ULK1 signaling pathway mediates the autophagy-promoting and osteogenic effects of dicalcium silicate nanoparticles

Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer

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