EP4-induced mitochondrial localization and cell migration mediated by CALML6 in human oral squamous cell carcinoma.
Commun Biol
; 7(1): 567, 2024 May 14.
Article
em En
| MEDLINE
| ID: mdl-38745046
ABSTRACT
Lymph node metastasis, primarily caused by the migration of oral squamous cell carcinoma (OSCC) cells, stands as a crucial prognostic marker. We have previously demonstrated that EP4, a subtype of the prostaglandin E2 (PGE2) receptor, orchestrates OSCC cell migration via Ca2+ signaling. The exact mechanisms by which EP4 influences cell migration through Ca2+ signaling, however, is unclear. Our study aims to clarify how EP4 controls OSCC cell migration through this pathway. We find that activating EP4 with an agonist (ONO-AE1-473) increased intracellular Ca2+ levels and the migration of human oral cancer cells (HSC-3), but not human gingival fibroblasts (HGnF). Further RNA sequencing linked EP4 to calmodulin-like protein 6 (CALML6), whose role remains undefined in OSCC. Through protein-protein interaction network analysis, a strong connection is identified between CALML6 and calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), with EP4 activation also boosting mitochondrial function. Overexpressing EP4 in HSC-3 cells increases experimental lung metastasis in mice, whereas inhibiting CaMKK2 with STO-609 markedly lowers these metastases. This positions CaMKK2 as a potential new target for treating OSCC metastasis. Our findings highlight CALML6 as a pivotal regulator in EP4-driven mitochondrial respiration, affecting cell migration and metastasis via the CaMKK2 pathway.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Ligação ao Cálcio
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Neoplasias Bucais
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Carcinoma de Células Escamosas
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Movimento Celular
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Receptores de Prostaglandina E Subtipo EP4
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Mitocôndrias
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article