14-3-3 and Smad2/3 Are Crucial Mediators of Atypical-PKCs: Implications for Neuroblastoma Progression

Overview

Journal Front Oncol

Specialty Oncology

Date 2023 Feb 13

PMID 36776326

Authors

S Breedy

W S Ratnayake

L Lajmi

R Hill

M Acevedo-Duncan

Affiliations

Soon will be listed here.

Abstract

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-ι promotes cell proliferation in NB cells through the PKC-ι/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-ι-specific 5-amino-1-2,3-dihydroxy-4-(methylcyclopentyl)-1H-imidazole-4-carboxamide and a PKC-ζ 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-κB and TGF-β pathways. Data indicates that aPKCs upregulate Akt1/NF-κB and TGF-β 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.

References

Scotti M, Bamlet W, Smyrk T, Fields A, Murray N . Protein kinase Ciota is required for pancreatic cancer cell transformed growth and tumorigenesis. Cancer Res. 2010; 70(5):2064-74. PMC: 2881466. DOI: 10.1158/0008-5472.CAN-09-2684. View

Corey J, Gertz C, Sutton T, Chen Q, Mycek K, Wang B . Patterning N-type and S-type neuroblastoma cells with Pluronic F108 and ECM proteins. J Biomed Mater Res A. 2009; 93(2):673-86. PMC: 2845720. DOI: 10.1002/jbm.a.32485. View

Xu J, Acharya S, Sahin O, Zhang Q, Saito Y, Yao J . 14-3-3ζ turns TGF-β's function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2. Cancer Cell. 2015; 27(2):177-92. PMC: 4325275. DOI: 10.1016/j.ccell.2014.11.025. View

Gautier M, Thirant C, Delattre O, Janoueix-Lerosey I . Plasticity in Neuroblastoma Cell Identity Defines a Noradrenergic-to-Mesenchymal Transition (NMT). Cancers (Basel). 2021; 13(12). PMC: 8230375. DOI: 10.3390/cancers13122904. View

Lu Z, Liu D, Hornia A, Devonish W, Pagano M, Foster D . Activation of protein kinase C triggers its ubiquitination and degradation. Mol Cell Biol. 1998; 18(2):839-45. PMC: 108795. DOI: 10.1128/MCB.18.2.839. View

Hurd T, Fan S, Liu C, Kweon H, Hakansson K, Margolis B . Phosphorylation-dependent binding of 14-3-3 to the polarity protein Par3 regulates cell polarity in mammalian epithelia. Curr Biol. 2003; 13(23):2082-90. DOI: 10.1016/j.cub.2003.11.020. View

Gunaratne A, Thai B, Di Guglielmo G . Atypical protein kinase C phosphorylates Par6 and facilitates transforming growth factor β-induced epithelial-to-mesenchymal transition. Mol Cell Biol. 2012; 33(5):874-86. PMC: 3623079. DOI: 10.1128/MCB.00837-12. View

Murray N, Kalari K, Fields A . Protein kinase Cι expression and oncogenic signaling mechanisms in cancer. J Cell Physiol. 2010; 226(4):879-87. PMC: 3075823. DOI: 10.1002/jcp.22463. View

Van Der Hoeven P, Van Der Wal J, Ruurs P, van Dijk M, Van Blitterswijk J . 14-3-3 isotypes facilitate coupling of protein kinase C-zeta to Raf-1: negative regulation by 14-3-3 phosphorylation. Biochem J. 2000; 345 Pt 2:297-306. PMC: 1220759. DOI: 10.1042/0264-6021:3450297. View

10.

Cui J, Song Y, Han X, Hu J, Chen Y, Chen X . Targeting 14-3-3ζ Overcomes Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Lung Adenocarcinoma via BMP2/Smad/ID1 Signaling. Front Oncol. 2020; 10:542007. PMC: 7571474. DOI: 10.3389/fonc.2020.542007. View

11.

Larochelle S, Merrick K, Terret M, Wohlbold L, Barboza N, Zhang C . Requirements for Cdk7 in the assembly of Cdk1/cyclin B and activation of Cdk2 revealed by chemical genetics in human cells. Mol Cell. 2007; 25(6):839-50. PMC: 1858677. DOI: 10.1016/j.molcel.2007.02.003. View

12.

Mendez M, Kojima S, Goldman R . Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J. 2010; 24(6):1838-51. PMC: 2874471. DOI: 10.1096/fj.09-151639. View

13.

Pillai P, Desai S, Patel R, Sajan M, Farese R, Ostrov D . A novel PKC-ι inhibitor abrogates cell proliferation and induces apoptosis in neuroblastoma. Int J Biochem Cell Biol. 2011; 43(5):784-94. DOI: 10.1016/j.biocel.2011.02.002. View

14.

Ponzoni M, Bachetti T, Corrias M, Brignole C, Pastorino F, Calarco E . Recent advances in the developmental origin of neuroblastoma: an overview. J Exp Clin Cancer Res. 2022; 41(1):92. PMC: 8915499. DOI: 10.1186/s13046-022-02281-w. View

15.

In Yook J, Li X, Ota I, Hu C, Kim H, Kim N . A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol. 2006; 8(12):1398-406. DOI: 10.1038/ncb1508. View

16.

Hu J, Han J, Li H, Zhang X, Liu L, Chen F . Human Embryonic Kidney 293 Cells: A Vehicle for Biopharmaceutical Manufacturing, Structural Biology, and Electrophysiology. Cells Tissues Organs. 2018; 205(1):1-8. DOI: 10.1159/000485501. View

17.

Wu Y, Deng J, Rychahou P, Qiu S, Evers B, Zhou B . Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell. 2009; 15(5):416-28. PMC: 2881229. DOI: 10.1016/j.ccr.2009.03.016. View

18.

Ratnayake W, Apostolatos C, Apostolatos A, Schutte R, Huynh M, Ostrov D . Oncogenic PKC-ι activates Vimentin during epithelial-mesenchymal transition in melanoma; a study based on PKC-ι and PKC-ζ specific inhibitors. Cell Adh Migr. 2018; 12(5):447-463. PMC: 6363030. DOI: 10.1080/19336918.2018.1471323. View

19.

Ratnayake W, Apostolatos C, Breedy S, Dennison C, Hill R, Acevedo-Duncan M . Atypical PKCs activate Vimentin to facilitate prostate cancer cell motility and invasion. Cell Adh Migr. 2021; 15(1):37-57. PMC: 7889213. DOI: 10.1080/19336918.2021.1882782. View

20.

Colon N, Chung D . Neuroblastoma. Adv Pediatr. 2011; 58(1):297-311. PMC: 3668791. DOI: 10.1016/j.yapd.2011.03.011. View