Non-canonical GLI1/2 activation by PI3K/AKT signaling in renal cell carcinoma: A novel potential therapeutic target

Zhou, Jiancheng; Zhu, Guodong; Huang, Jun; Li, Lei; Du, Yifan; Gao, Yang; Wu, Dapeng; Wang, Xinyang; Hsieh, Jer Tsong; He, Dalin; Wu, Kaijie

doi:10.1016/j.canlet.2015.11.006

Cited by 92 publications

(96 citation statements)

References 49 publications

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“…Specifically, Gli1 expression was inversely associated with the expression of the EMT markers E-cadherin and β-catenin in lung cancer specimens (36). Moreover, the excessive activation of the SHH signaling pathway was directly related to the nervous system and other cancers (37,38). Souzaki et al found that most patients with neuroblastoma who did not exhibit v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) amplification were positive for Shh, Gli1, and Ptch1.…”

Section: Discussionmentioning

confidence: 99%

The mechanism of epithelial-mesenchymal transition induced by TGF-β1 in neuroblastoma cells

Shao

Gao

Huang

et al. 2017

International Journal of Oncology

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Neuroblastoma is the second most common extracranial malignant solid tumor that occurs in childhood, and metastasis is one of the major causes of death in neuroblastoma patients. The epithelial-mesenchymal transition (EMT) is an important mechanism for both the initiation of tumor invasion and subsequent metastasis. Therefore, this study investigated the mechanism by which transforming growth factor (TGF)-β1 induces EMT in human neuroblastoma cells. Using quantitative RT-qPCR and western blot analyses, we found that the mRNA and protein expression levels of E-cadherin were significantly decreased, whereas that of α-SMA was significantly increased after neuroblastoma cells were treated with different concentrations of TGF-β1. A scratch test and Transwell migration assay revealed that cell migration significantly and directly correlated with the concentration of TGF-β1 indicating that TGF-β1 induced EMT in neuroblastoma cells and led to their migration. Inhibiting Smad2/3 expression did not affect the expression of the key molecules involved in EMT. Further investigation found that the expression of the glioblastoma transcription factor (Gli) significantly increased in TGF-β1-stimulated neuroblastoma cells undergoing EMT, accordingly, interfering with Gli1/2 expression inhibited TGF-β1-induced EMT in neuroblastoma cells. GANT61, which is a targeted inhibitor of Gli1 and Gli2, decreased cell viability and promoted cell apoptosis. Thus, TGF-β1 induced EMT in neuroblastoma cells to increase their migration. Specifically, EMT induced by TGF-β1 in neuroblastoma cells did not depend on the Smad signaling pathway, and the transcription factor Gli participated in TGF-β1-induced EMT independent of Smad signaling.

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Section: Discussionmentioning

confidence: 99%

The mechanism of epithelial-mesenchymal transition induced by TGF-β1 in neuroblastoma cells

Shao

Gao

Huang

et al. 2017

International Journal of Oncology

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“…Gli1 can be regulated by specific serine/threonine kinases (34,(36)(37)(38), and we have demonstrated that DGT inhibits GSK3b activity, which are known to be associated with osteosarcoma progression and poor patient outcome. Therefore, we hypothesized that GSK3b activity is involved in DGT-induced Gli1 repression in osteosarcoma.…”

Section: Dgt Downregulates Gli1 Expression and Activation Mainly By Bmentioning

confidence: 99%

Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation–Mediated Repression of the Hedgehog/Gli1 Pathway

Zhao

Jia

et al. 2018

Clinical Cancer Research

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Purpose: Agents extracted from natural sources with antitumor property have attracted considerable attention from researchers and clinicians because of their safety, efficacy, and immediate availability. Degalactotigonin (DGT), extracted from Solanum nigrum L., has anticancer properties without serious side effects. Here, we explored whether DGT can inhibit the growth and metastasis of osteosarcoma.Experimental Design: MTT, colony formation, and apoptosis assays were performed to analyze the effects of DGT on osteosarcoma cell viability in vitro. The migration and invasion abilities were measured using a Transwell assay. Animal models were used to assess the roles of DGT in both tumor growth and metastasis of osteosarcoma. Gli1 expression and function were measured in osteosarcoma cells and clinical samples. After DGT treatment, Gli1 activation and the phosphorylation status of multiple cellular kinases were measured with a luciferase reporter and phospho-kinase antibody array.Results: DGT inhibited proliferation, induced apoptosis, and suppressed migration and invasion in osteosarcoma cells. DGT, injected intraperitoneally after tumor inoculation, significantly decreased the volume of osteosarcoma xenografts and dramatically diminished the occurrence of osteosarcoma xenograft metastasis to the lungs. Mechanistically, DGT inhibited osteosarcoma growth and metastasis through repression of the Hedgehog/Gli1 pathway, which maintains malignant phenotypes and is involved in the prognosis of osteosarcoma patients. DGT decreased the activity of multiple intracellular kinases that affect the survival of osteosarcoma patients, including GSK3b. In addition, DGT represses the Hedgehog/Gli1 pathway mainly through GSK3b inactivation.Conclusions: Our studies provide evidence that DGT can suppress the growth and metastasis of human osteosarcoma through modulation of GSK3b inactivation-mediated repression of the Hedgehog/Gli1 pathway.

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“…An additional report suggests that crosstalk between GLI1 and PI3K/AKT/NF-κB renders AML cells resistant to radiation [20]. Non-canonical upregulation of the GLI transcription factors has been described for a number of oncogenic pathways including TGF-β, RAS/RAF/MEK/MAPK, ERBB2, PI3K/AKT and mTOR [9–11, 21–23]. We could recently show that GLI1 is activated via ERBB2 and PI3K/AKT/mTOR in esophageal adenocarcinoma in a SMO-independent manner [10].…”

Section: Discussionmentioning

confidence: 99%

“…We could recently show that GLI1 is activated via ERBB2 and PI3K/AKT/mTOR in esophageal adenocarcinoma in a SMO-independent manner [10]. Another group could demonstrate a non-canonical activation of GLI1 in esophageal adenocarcinoma via TNF-α and subsequently mTOR/S6K1 [21] while Zhou and colleagues could recently show that GLI1 and GLI2 are non-canonically activated via PI3K/AKT in human renal cell carcinoma [9]. Using GLI Reporter cell lines, we could show that an active GLI signaling cascade in AML cells is mainly SMO-independent as the treatment with the SMO inhibitor cyclopamine had hardly any impact on the GLI promoter activity of all six analyzed AML cell lines.…”

Section: Discussionmentioning

confidence: 99%

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Combined inhibition of GLI and FLT3 signaling leads to effective anti-leukemic effects in human acute myeloid leukemia

et al. 2017

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Activation of the Hedgehog pathway has been implicated in the pathogenesis of several tumor types including myeloid leukemia. Previously we demonstrated that overexpression of Hedgehog downstream mediators GLI1/2 confers an adverse prognosis to patients with acute myeloid leukemia (AML) and is correlated with a FLT3 mutated status. To analyze a possible non-canonical activation of the Hedgehog pathway via FLT3 and PI3K, we performed blocking experiments utilizing inhibitors for FLT3 (sunitinib), PI3K (PF-04691502) and GLI1/2 (GANT61) in FLT3-mutated and FLT3 wildtype AML cell lines and primary blasts. Combination of all three compounds had stronger anti-leukemic effects in FLT3-mutated compared to FLT3 wildtype AML cells in vitro. Interestingly, the colony growth of normal CD34+ cells from healthy donors was not impeded by the triple inhibitor combination possibly opening a therapeutic window for the clinical use of inhibitor combinations. Besides, combined treatment with sunitinib, PF-04691502 and GANT61 significantly prolonged the survival of mice transplanted with FLT3-mutated MV4-11 cells compared to the single agent treatments. Furthermore, the inhibition of FLT3 and PI3K resulted in reduced GLI protein expression and promotor activity in FLT3-mutated but not in FLT3 wildtype AML cell lines in western blotting and GLI1/2 promoter assays supporting our hypothesis of non-canonical GLI activation via FLT3.In summary, FLT3-mutated in contrast to FLT3 wildtype cells or normal human hematopoietic progenitor cells are exquisitely sensitive to combined inhibition by FLT3, PI3K and GLI1/2 overcoming some of the limitations of current FLT3 directed therapy in AML. The development of GLI1/2 inhibitors is highly desirable.

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Non-canonical GLI1/2 activation by PI3K/AKT signaling in renal cell carcinoma: A novel potential therapeutic target

Cited by 92 publications

References 49 publications

The mechanism of epithelial-mesenchymal transition induced by TGF-β1 in neuroblastoma cells

The mechanism of epithelial-mesenchymal transition induced by TGF-β1 in neuroblastoma cells

Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation–Mediated Repression of the Hedgehog/Gli1 Pathway

Combined inhibition of GLI and FLT3 signaling leads to effective anti-leukemic effects in human acute myeloid leukemia

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