4.6 Article

14-3-3 and Smad2/3 are crucial mediators of atypical-PKCs: Implications for neuroblastoma progression

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FRONTIERS IN ONCOLOGY
卷 13, 期 -, 页码 -

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FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2023.1051516

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PKC-iota; PKC-zeta; 14-3-3; Smad2; 3; neuroblastoma; targeted therapy

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Neuroblastoma is a common cancer in children under the age of 1 and has varying prognosis based on age and cell differentiation. Our study identified two protein kinase inhibitors with potential therapeutic effects against NB cells. These inhibitors induced cell apoptosis and inhibited EMT. The Akt1/NF-κB and TGF-β pathways were found to be regulated by aPKCs, and their association with 14-3-3 and Smad2/3 could be diminished by aPKC inhibitors. Both inhibitors show promise as neuroblastoma therapeutics and require further research.
Neuroblastoma (NB) is a cancer that develops in the neuroblasts. It is the most common cancer in children under the age of 1 year, accounting for approximately 6% of all cancers. The prognosis of NB is linked to both age and degree of cell differentiation. This results in a range of survival rates for patients, with outcomes ranging from recurrence and mortality to high survival rates and tumor regression. Our previous work indicated that PKC-iota promotes cell proliferation in NB cells through the PKC-iota/Cdk7/Cdk2 cascade. We report on two atypical protein kinase inhibitors as potential therapeutic candidates against BE(2)-C and BE(2)-M17 cells: a PKC-iota-specific 5-amino-1-2,3-dihydroxy-4-(methylcyclopentyl)-1H-imidazole-4-carboxamide and a PKC-zeta specific 8-hydroxy-1,3,6-naphthalenetrisulfonic acid. Both compounds induced apoptosis and retarded the epithelial-mesenchymal transition (EMT) of NB cells. Proteins 14-3-3 and Smad2/3 acted as central regulators of aPKC-driven progression in BE(2)-C and BE(2)-M17 cells in relation to the Akt1/NF-kappa B and TGF-beta pathways. Data indicates that aPKCs upregulate Akt1/NF-kappa B and TGF-beta pathways in NB cells through an association with 14-3-3 and Smad2/3 that can be diminished by aPKC inhibitors. In summary, both inhibitors appear to be promising potential neuroblastoma therapeutics and merit further research.

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