The Crosstalk of mTOR/S6K1 and Hedgehog Pathways

Wang, Yan; Ding, Qingqing; Yen, Chia Jui; Xia, Weiya; Izzo, Julie; Lang, Jing Yu; Li, Chia Wei; Hsu, Jennifer L.; Miller, Stephanie A.; Wang, Xuemei; Lee, Dung‐Fang; Hsu, Jung Mao; Huo, Longfei; LaBaff, Adam M.; Liu, Dongping; Huang, Tzu Hsuan; Lai, Chien‐Chen; Tsai, Fuu Jen; Chang, Wei Chao; Chen, Chung Hsuan; Wu, Tsung Teh; Buttar, Navtej; Wang, Kenneth K.; Wu, Yun; Wang, Huamin; Ajani, Jaffer A.; Hung, Mien Chie

doi:10.1016/j.ccr.2011.12.028

Cited by 321 publications

(383 citation statements)

References 43 publications

Supporting

Mentioning

366

Contrasting

Unclassified

Order By: Relevance

“…Our results show that DGT inhibits activation of GSK3b by increasing the phosphorylation level. Gli1 has been reported to be activated by many kinases, such as AKT, MAPK/ERK, and mTOR/S6K1 (42,47). In this study, we were able to show a link between GSK3b and Gli1.…”

Section: Discussionsupporting

confidence: 66%

“…The HH signal pathway is also considered to be crucially involved in the development and progression of many cancers because it is overactivated and correlated with growth and metastasis (36,42,43). Activated Gli proteins, primarily Gli1, translocate into the nucleus and stimulate the transcription of HH pathway target genes, including Gli1, PTCH1, and many survival-promoting molecules (44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…As well, the S6K1 pathway is related to Gli1-mediated proliferation of esophageal adenocarcinoma cells, supporting the role of S6K1 in cancer cell proliferation. 23,24 In addition, cell cycle progression was severely blocked in liverspecific S6 knockout mice after hepatectomy, 25 indicating the critical role of S6 in cell cycle progression. At present, it remains unclear how S6 and its phosphorylation control cell cycle regulators in esophageal cancer.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance and function of phosphorylated ribosomal protein S6 in esophageal squamous cell carcinoma

et al. 2013

View full text Add to dashboard Cite

Ribosomal protein S6 is a key regulator of 40S ribosome biogenesis, and its phosphorylation is closely related to cell growth capacity. However, as a downstream target of S6 kinases, the clinical significance and the roles of S6 and S6 phosphorylation in cell viability and motility of esophageal squamous cell carcinoma remain unclear. Here, we show that high level of phosphorylated-ribosomal protein S6 (p-S6) (immunohistochemistry score Z5) and an increased ratio of p-S6/S6 (immunohistochemistry score Z0.75) were significantly associated with shortened disease-free survival in patients with esophageal squamous cell carcinoma in univariate analysis (P ¼ 0.049 and Po0.001, respectively). After adjusting for age, tumor-nodes-metastasis stage, chemotherapy, and radiation therapy in multivariate analysis, both p-S6 (hazard ratio 2.21, P ¼ 0.005) and p-S6/S6 (hazard ratio 2.40, Po0.001) remained independent adverse prognostic factors. In addition, S6 and S6 kinase 1 knockdown resulted in attenuation of viability by suppressing cyclin D1 expression in esophageal cancer cells. Furthermore, depletion of S6 and S6 kinase 1 resulted in a reduction in esophageal cancer cell migration and invasion. This was paralleled by a reduction in focal adhesion and by suppression of extracellular signal-regulated kinase and c-jun N-terminal kinase phosphorylation, which control cell motility. Collectively, these findings suggest that p-S6 and the ratio of p-S6/S6 are closely relevant to tumor progression and have prognostic significance in esophageal squamous cell carcinoma. Modern Pathology (2013) 26, 327-335; doi:10.1038/modpathol.2012.161; published online 21 September 2012Keywords: esophagus squamous cell carcinoma; phosphorylation; S6 Esophageal squamous cell carcinoma is one of the most aggressive malignant tumors of the gastrointestinal tract, and has a high mortality rate. 1 The prognosis of esophagus squamous cell carcinoma is poor due to a high incidence of metastasis to lymph nodes, liver, and lung. 1 Despite the development of multimodal therapies including surgery, chemotherapy, radiotherapy, and chemo-radiotherapy, the 5-year survival rate of patients remains in the range of 10 to 25%, 1 underscoring the need for identifying the signaling pathways and downstream targets that lead to esophageal cancer progression and metastasis. 2,3 Recently, the mammalian target of rapamycin (mTOR)-S6 kinase (S6K1) signaling pathway-has emerged as a critical regulator of cellular metabolism, proliferation, and survival in response to growth factor and nutrient availability. [4][5][6][7] Upon growth factor stimulation, mTOR-dependent activation of S6K1 induces phosphorylation of S6, the 40S ribosomal protein at Ser235, Ser236, Ser240, Ser244, and Ser247. 8,9 The importance of S6 phosphorylation is underscored by the finding that mouse embryonic fibroblasts from S6 knock-in mice in which all phosphorylatable serine residues in S6 are substituted by alanines exhibit small cell size, 10 indicating the potential role of S6 phosphorylation in r...

show abstract

“…Activated Gli proteins eventually translocate into the nucleus and trigger the transcription of downstream target genes (5,7). In addition to classical HH signal transduction, the non-canonical HH pathway, in which Gli proteins are regulated by phosphoinositide 3-kinase (PI3K)/V-Akt murine thymoma viral oncogene (Akt), mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK), nuclear factor κB (NF-κB) and/or transforming growth factor β (TGFβ) pathways as well as the key tumor suppressors tumor protein p53 (TP53) and phosphatase and tensin homolog (PTEN) in a ligand-independent manner, has been the focus of previous research (8)(9)(10). Although the canonical pathway has been well-investigated, how Gli proteins are regulated in a SMO-independent manner in prostate cancer remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Gli1‑mediated prostate cancer cell proliferation by inhibiting the mTOR/S6K1 signaling pathway

Yang

Liu

et al. 2017

Oncol Lett

View full text Add to dashboard Cite

Abstract. Ectopic activation of the canonical Hedgehog signaling pathway is involved in the development and progression of prostate cancer, which is one of the leading causes of cancer-associated mortality in males worldwide. However, the role of the non-canonical Hedgehog signaling pathway in prostate cancer remains generally unexplored. In the present study, it was identified that Gli (glioma-associated oncogene)1 and Gli2 were highly expressed at the protein level in the androgen-independent prostate cancer cell lines PC3 and DU145, but not in the androgen-dependent cancer cell line LNCaP. Silencing of Gli1 using small interfering RNA markedly decreased PC3 cell viability and liquid colony formation in vitro. The Gli1/2-specific inhibitor GANT61 markedly decreased cell viability by inducing cell apoptosis in PC3 and DU145 cells. GANT61 also alleviated liquid colony formation efficiency in PC3 and DU145 cells, suggesting that the activity of Gli1 is required for prostate cancer cell survival. To explore further the upstream signaling pathway involved in the regulation of Gli1 expression, it was identified that tumor necrosis factor α-triggered mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase 1 (S6K1) activation was required for Gli1 expression. Pharmacological and genetic inhibition of S6K1 activation markedly decreased Gli1 and its downstream target gene mRNA expression. In addition, the phosphoinositide 3-kinase/mTOR inhibitor BEZ235 markedly decreased in vitro PC3 cell proliferation. The results of the present study indicate that the non-canonical Hedgehog pathway (mTOR/S6K1/Gli1) contributes to the development and progression of prostate cancer and that Gli1 is a potential therapeutic target in the treatment of prostate cancer.

show abstract

The Crosstalk of mTOR/S6K1 and Hedgehog Pathways

Cited by 321 publications

References 43 publications

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

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

Prognostic significance and function of phosphorylated ribosomal protein S6 in esophageal squamous cell carcinoma

Inhibition of Gli1‑mediated prostate cancer cell proliferation by inhibiting the mTOR/S6K1 signaling pathway

Contact Info

Product

Resources

About