Anaplastic Lymphoma Kinase signaling stabilizes SLC3A2 expression via MARCH11 to promote neuroblastoma cell growth.
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
10 Jun 2024
10 Jun 2024
Historique:
received:
01
10
2023
accepted:
28
05
2024
revised:
23
05
2024
medline:
11
6
2024
pubmed:
11
6
2024
entrez:
10
6
2024
Statut:
aheadofprint
Résumé
Solute Carrier Family 3, Member 2 (SLC3A2 or 4F2hc) is a multifunctional glycoprotein that mediates integrin-dependent signaling, acts as a trafficking chaperone for amino acid transporters, and is involved in polyamine transportation. We identified SLC3A2 as a potential Anaplastic Lymphoma Kinase (ALK) interacting partner in a BioID-proximity labeling screen in neuroblastoma (NB) cells. In this work we show that endogenous SLC3A2 and ALK interact in NB cells and that this SLC3A2:ALK interaction was abrogated upon treatment with the ALK inhibitor lorlatinib. We show here that loss of ALK activity leads to decreased SLC3A2 expression and reduced SLC3A2 protein stability in a panel of NB cell lines, while stimulation of ALK with ALKAL2 ligand resulted in increased SLC3A2 protein levels. We further identified MARCH11, an E3 ligase, as a regulator of SLC3A2 ubiquitination downstream of ALK. Further, knockdown of SLC3A2 resulted in inhibition of NB cell growth. To investigate the therapeutic potential of SLC3A2 targeting, we performed monotreatment of NB cells with AMXT-1501 (a polyamine transport inhibitor), which showed only moderate effects in NB cells. In contrast, a combination lorlatinib/AMXT-1501 treatment resulted in synergistic inhibition of cell growth in ALK-driven NB cell lines. Taken together, our results identify a novel role for the ALK receptor tyrosine kinase (RTK), working in concert with the MARCH11 E3 ligase, in regulating SLC3A2 protein stability and function in NB cells. The synergistic effect of combined ALK and polyamine transport inhibition shows that ALK/MARCH11/SLC3A2 regulation of amino acid transport is important for oncogenic growth and survival in NB cells.
Identifiants
pubmed: 38858548
doi: 10.1038/s41418-024-01319-0
pii: 10.1038/s41418-024-01319-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Cancerfonden (Swedish Cancer Society)
ID : CAN21/1525
Organisme : Cancerfonden (Swedish Cancer Society)
ID : CAN21/1459
Organisme : Vetenskapsrådet (Swedish Research Council)
ID : 2021-01192
Organisme : Vetenskapsrådet (Swedish Research Council)
ID : 2019-03914
Organisme : Barncancerfonden (Swedish Childhood Cancer Foundation)
ID : PR2021-27
Organisme : Barncancerfonden (Swedish Childhood Cancer Foundation)
ID : PR2022-0029
Informations de copyright
© 2024. The Author(s).
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