Activation of AMPK sensitizes medulloblastoma to Vismodegib and overcomes Vismodegib‐resistance

et al. 2023

Cell Biosci

Background Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Metastasis and relapse are the leading causes of death in MB patients. The initiation of the SHH subgroup of MB (SHH-MB) is due to the aberrant activation of Sonic Hedgehog (Shh) signaling. However, the mechanisms for its metastasis are still unknown. Results AMP-dependent protein kinase (AMPK) restrains the activation of Shh signaling pathway, thereby impeding the proliferation of SHH-MB cells. More importantly, AMPK also hinders the growth and metastasis of SHH-MB cells by regulating NF-κB signaling pathway. Furthermore, Vismodegib and TPCA-1, which block the Shh and NF-κB pathways, respectively, synergistically restrained the growth, migration, and invasion of SHH-MB cells. Conclusions This work demonstrates that AMPK functions through two signaling pathways, SHH-GLI1 and NF-κB. AMPK-NF-κB axis is a potential target for molecular therapy of SHH-MB, and the combinational blockade of NF-κB and Shh pathways confers synergy for SHH-MB therapy.

Section: Resultsmentioning

confidence: 99%

AMPK attenuates SHH subgroup medulloblastoma growth and metastasis by inhibiting NF-κB activation

Cai

et al. 2023

Cell Biosci

“…To identify small molecules facilitating the induction of NCCs to differentiate into CEC destined cells, we built a chemical library of 30 small molecules that targeted almost all the key pathways of stem cell differentiation and corneal development ( Table 1 ). The final concentration of each compound added to the medium was based on previously reported data and testing for the ED50s in the NCCs via Cell Counting Kit-8 (CCK-8) assay ( Miner et al, 2003 ; Bouzakri et al, 2004 ; Moreno et al, 2008 ; Johnson et al, 2012 ; Yap et al, 2012 ; Cho et al, 2013 ; Han et al, 2014 ; Schelleman et al, 2014 ; Kampa-Schittenhelm et al, 2017 ; Pinkosky et al, 2020 ; Zhang et al, 2020 ; Gampala et al, 2021 ; Ma et al, 2021 ). For initial screening, NCCs derived from dual-SMAD inhibition of hiPSCs for 6 days were cultured in a 24-well plate and treated with small molecules for another 3 days.…”

Section: Resultsmentioning

confidence: 99%

Small-Molecule Induction Promotes Corneal Endothelial Cell Differentiation From Human iPS Cells

Chen

Front. Bioeng. Biotechnol.

et al. 2021

Purpose: Corneal endothelial cells (CECs) serve as a barrier and foothold for the corneal stroma to maintain the function and transparency of the cornea. Loss of CECs during aging or disease states leads to blindness, and cell replacement therapy using either donated or artificially differentiated CECs remains the only curative approach.Methods: Human induced pluripotent stem cells (hiPSCs) that were cultured in chemically defined medium were induced with dual-SMAD inhibition to differentiate into neural crest cells (NCCs). A small-molecule library was screened to differentiate the NCCs into corneal endothelial-like cells. The characteristics of these cells were identified with real-time PCR and immunofluorescence. Western blotting was applied to detect the signaling pathways and key factors regulated by the small molecules.Results: We developed an effective protocol to differentiate hiPSCs into CECs with defined small molecules. The hiPSC-CECs were characterized by ZO-1, AQP1, Vimentin and Na+/K+-ATPase. Based on our small-molecule screen, we identified a small-molecule combination, A769662 and AT13148, that enabled the most efficient production of CECs. The combination of A769662 and AT13148 upregulated the PKA/AKT signaling pathway, FOXO1 and PITX2 to promote the conversion of NCCs to CECs.Conclusion: We established an efficient small molecule-based method to differentiate hiPSCs into corneal endothelial-like cells, which might facilitate drug discovery and the development of cell-based therapies for corneal diseases.

“…Considering the low expression of AMPK in metastatic MB, we sought to explore the novel molecular targets of MB therapy at the downstream of AMPK (29). AMPK-NF-κB axis functions in the metastasis of SHH-MB.…”

Section: Discussionmentioning

confidence: 99%

“…Although it was reported that activation of AMPK suppresses MB cell growth through inhibition of GLI1 activity and expression by phosphorylating and destabilizing GLI1 protein (20)…”

Section: Ampk-gli1 Inhibits Daoy Cell Growth But Not Metastasismentioning

confidence: 99%

AMPK attenuates SHH subgroup medulloblastoma growth and metastasis by inhibiting NF-κB activation

Yue

Cai

et al. 2022

Preprint

Background: Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Metastasis and relapse are the leading causes of death in MB patients. The initiation of the SHH subgroup of MB (SHH-MB) is due to the aberrant activation of Sonic Hedgehog (Shh) signaling. However, the mechanisms for its metastasis are still unknown. Results: AMP-dependent protein kinase (AMPK) restrains the activation of Shh signaling pathway, thereby impeding the proliferation of SHH-MB cells. More importantly, AMPK also hinders the growth and metastasis of SHH-MB cells by regulating NF-κB signaling pathway. Furthermore, Vismodegib and TPCA-1, which block the Shh and NF-κB pathways, respectively, synergistically restrained the growth, migration, and invasion of SHH-MB cells. Conclusions: This work demonstrates that AMPK functions through two signaling pathways, SHH-GLI1 and NF-κB. AMPK-NF-κB axis is a potential target for molecular therapy of SHH-MB, and the combinational blockade of NF-κB and Shh pathways confers synergy for SHH-MB therapy.