Soloxolone Methyl Reduces the Stimulatory Effect of Leptin on the Aggressive Phenotype of Murine Neuro2a Neuroblastoma Cells via the MAPK/ERK1/2 Pathway Full article
| Journal |
Pharmaceuticals
ISSN: 1424-8247 |
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| Output data | Year: 2023, Volume: 16, Article number : 1369, Pages count : DOI: 10.3390/ph16101369 | ||||
| Tags | leptin; neuroblastoma; adipokines; aggressiveness; triterpenoids; EMT; molecular docking | ||||
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| Affiliations |
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Funding (1)
| 1 | Russian Science Foundation | РНФ №23-14-00374 |
Abstract:
Despite the proven tumorigenic effect of leptin on epithelial-derived cancers, its impact
on the aggressiveness of neural crest-derived cancers, notably neuroblastoma, remains largely unexplored. In our study, for the first time, transcriptome analysis of neuroblastoma tissue demonstrated
that the level of leptin is elevated in neuroblastoma patients along with the severity of the disease
and is inversely correlated with patient survival. The treatment of murine Neuro2a neuroblastoma
cells with leptin significantly stimulated their proliferation and motility and reduced cell adhesion,
thus rendering the phenotype of neuroblastoma cells more aggressive. Given the proven efficacy
of cyanoenone-bearing semisynthetic triterpenoids in inhibiting the growth of neuroblastoma and
preventing obesity in vivo, the effect of soloxolone methyl (SM) on leptin-stimulated Neuro2a cells
was further investigated. We found that SM effectively abolished leptin-induced proliferation of
Neuro2a cells by inducing G1/S cell cycle arrest and restored their adhesiveness to extracellular
matrix (ECM) proteins to near control levels through the upregulation of vimentin, zonula occludens
protein 1 (ZO-1), cell adhesion molecule L1 (L1cam), and neural cell adhesion molecule 1 (Ncam1).
Moreover, SM significantly suppressed the leptin-associated phosphorylation of extracellular signalregulated kinase 1/2 (ERK1/2) and ribosomal protein S6 kinase A1 (p90RSK), which are key kinases
that ensure the survival and proliferation of cancer cells. Further molecular modeling studies demonstrated that the inhibitory effect of SM on the mitogen-activated protein kinase (MAPK)/ERK1/2
signaling pathway can be mediated by its direct interaction with ERK2 and its upstream regulators,
son of sevenless homolog 1 (SOS) and mitogen-activated protein kinase kinase 1 (MEK1). Taken
together, our findings in murine Neuro2a cells provide novel evidence of the stimulatory effect of
leptin on the aggressiveness of neuroblastoma, which requires further detailed studies in human neuroblastoma cells and relevant animal models. The obtained results indicate that SM can be considered
a promising drug candidate capable of reducing the impact of adipokines on tumor progression
Cite:
Odarenko K.V.
, Salomatina O.V.
, Chernikov I.V.
, Salakhutdinov N.F.
, Zenkova M.A.
, Markov A.V.
Soloxolone Methyl Reduces the Stimulatory Effect of Leptin on the Aggressive Phenotype of Murine Neuro2a Neuroblastoma Cells via the MAPK/ERK1/2 Pathway
Pharmaceuticals. 2023. V.16. 1369 . DOI: 10.3390/ph16101369 WOS Scopus PMID OpenAlex
Soloxolone Methyl Reduces the Stimulatory Effect of Leptin on the Aggressive Phenotype of Murine Neuro2a Neuroblastoma Cells via the MAPK/ERK1/2 Pathway
Pharmaceuticals. 2023. V.16. 1369 . DOI: 10.3390/ph16101369 WOS Scopus PMID OpenAlex
Dates:
| Published print: | Sep 27, 2023 |
Identifiers:
| Web of science: | WOS:001093596800001 |
| Scopus: | 2-s2.0-85175460873 |
| PMID: | 37895840 |
| OpenAlex: | W4387120979 |