mTORC1-Mediated Inhibition of 4EBP1 Is Essential for Hedgehog Signaling-Driven Translation and Medulloblastoma

Wu, Chang Chih; Hou, Shirui; Orr, Brent A.; Kuo, Bryan; Youn, Yong Ha; Ong, Taren; Roth, F; Eberhart, Charles G.; Robinson, Giles; Solecki, David J.; Taketo, Makoto Mark; Gilbertson, Richard J.; Roussel, Martine F.; Han, Young-Goo

doi:10.1016/j.devcel.2017.10.011

Cited by 55 publications

(64 citation statements)

References 75 publications

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“…This includes mechanistic target of rapamycin(mTOR) signaling, a metabolic pathway that has been shown to crosstalk with the IDO1 pathway in medulloblastoma 48 . mTOR promotes medulloblastoma tumor progression 49,50 and targeting mTOR may be a promising strategy to treat medulloblastoma 51 . Studies characterizing the molecular mechanisms and subgroup-specficity of 1-L-[ 18 F]FETrp uptake in medulloblastoma are currently in progress.…”

Section: Discussionmentioning

confidence: 99%

PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

Xin

Yue

et al. 2020

Sci Rep

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In vivo positron emission tomography (pet) imaging is a key modality to evaluate disease status of brain tumors. In recent years, tremendous efforts have been made in developing PET imaging methods for pediatric brain tumors. Carbon-11 labelled tryptophan derivatives are feasible as PET imaging probes in brain tumor patients with activation of the kynurenine pathway, but the short half-life of carbon-11 limits its application. Using a transgenic mouse model for the sonic hedgehog (Shh) subgroup of medulloblastoma, here we evaluated the potential of the newly developed 1-(2-[ 18 F]fluoroethyl)-L-tryptophan (1-L-[ 18 f]fetrp) as a pet imaging probe for this common malignant pediatric brain tumor. 1-L-[ 18 F]FETrp was synthesized on a PETCHEM automatic synthesizer with good chemical and radiochemical purities and enantiomeric excess values. Imaging was performed in tumor-bearing Smo/ Smo medulloblastoma mice with constitutive actvation of the Smoothened (Smo) receptor using a PerkinElmer G4 PET-X-Ray scanner. Medulloblastoma showed significant and specific accumulation of 1-L-[ 18 F]FETrp. 1-L-[ 18 F]FETrp also showed significantly higher tumor uptake than its D-enantiomer, 1-D-[ 18 F]FETrp. The uptake of 1-L-[ 18 F]FETrp in the normal brain tissue was low, suggesting that 1-L-[ 18 f] fetrp may prove a valuable pet imaging probe for the Shh subgroup of medulloblastoma and possibly other pediatric and adult brain tumors.

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Section: Discussionmentioning

confidence: 99%

PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

Xin

Yue

et al. 2020

Sci Rep

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“…4EBP1 is a downstream protein of mTOR, which inhibits eIF4E (the subunit of eIF4F). When 4EBP1 is in a low phosphorylation state, it inhibits the translation of mRNA by binding tightly with eIF4E while reducing interaction with cap-binding protein eIF4G to form the initial complex of eIF4F [32]. It is known that eIF4F controls the expression of many proteins that are associated with cell proliferation, expansion, and apoptosis, such as Mcl-1 (antiapoptotic molecule), cyclin D1 and D3 (cell-cycle regulators), and C-Myc (oncoprotein) [33,34].…”

Section: Discussionmentioning

confidence: 99%

In Vitro Investigation of The Cytotoxic Activity of E35 on Multiple Myeloma Cell Lines

Zheng¹,

Chen²,

Zheng³

et al. 2020

Preprint

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Background: Bortezomib is used for the treatment of multiple myeloma (MM); however, it has significant adverse effects. Emodin has been reported to exhibit inhibitory effects on MM cell lines. Here, we investigated the efficacy of E35, an emodin derivative, using U266 and MM1s cell lines in the treatment of MM and the efficacy of the combination of bortezomib and E35. Methods: MTT assays were used to observe the effects of E35 on MM cell growth. The effects on cellular apoptosis were observed using the Annexin V/propidium iodide (PI) staining assay. The expression of apoptosis-related genes, including the caspase family, was also examined. The efficacy of the combination of bortezomib and E35 was investigated by examining the expression of the Akt/mTOR/4EBP1 signaling pathway-related proteins. Results: We found that E35 inhibited the growth of the U266 and MM1s cells by inducing cellular apoptosis. E35 also downregulated the expression of the apoptosis-related genes and suppressed the phosphorylation of the Akt/mTOR/4EBP1 signaling pathway-related genes, exhibiting synergistic effects with bortezomib. All the observed effects were dose-dependent. Conclusion: The results of this study showed that E35 exhibited cytotoxic effects in MM cell lines. Thus, E35, especially in combination with bortezomib, may be considered as a promising treatment for MM. However, this requires further investigation in vivo.

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“…It was found that canonical Hh signaling required mTORC1-mediated inhibition of 4E-BP1, since the mTOR inhibitor Torin1 suppressed GLI1 mRNA induction in response to SAG, and KD of 4E-BP1 , by shRNAs, reversed the effect of Torin1 on GLI1 mRNA expression. Inhibition of mTORC1 further suppressed Hh-dependent growth of cerebellar and medulloblastoma [ 95 ]. It is interesting to note that Torin1 but not rapamycin could suppress SAG-mediated Hh signaling.…”

Section: Mechanisms Leading To Hh/mtor Crosstalkmentioning

confidence: 99%

Crosstalk of Hedgehog and mTORC1 Pathways

Larsen

Møller

2020

Cells

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Hedgehog (Hh) signaling and mTOR signaling, essential for embryonic development and cellular metabolism, are both coordinated by the primary cilium. Observations from cancer cells strongly indicate crosstalk between Hh and mTOR signaling. This hypothesis is supported by several studies: Evidence points to a TGFβ-mediated crosstalk; Increased PI3K/AKT/mTOR activity leads to increased Hh signaling through regulation of the GLI transcription factors; increased Hh signaling regulates mTORC1 activity positively by upregulating NKX2.2, leading to downregulation of negative mTOR regulators; GSK3 and AMPK are, as members of both signaling pathways, potentially important links between Hh and mTORC1 signaling; The kinase DYRK2 regulates Hh positively and mTORC1 signaling negatively. In contrast, both positive and negative regulation of Hh has been observed for DYRK1A and DYRK1B, which both regulate mTORC1 signaling positively. Based on crosstalk observed between cilia, Hh, and mTORC1, we suggest that the interaction between Hh and mTORC1 is more widespread than it appears from our current knowledge. Although many studies focusing on crosstalk have been carried out, contradictory observations appear and the interplay involving multiple partners is far from solved.

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mTORC1-Mediated Inhibition of 4EBP1 Is Essential for Hedgehog Signaling-Driven Translation and Medulloblastoma

Cited by 55 publications

References 75 publications

PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

In Vitro Investigation of The Cytotoxic Activity of E35 on Multiple Myeloma Cell Lines

Crosstalk of Hedgehog and mTORC1 Pathways

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