p140Cap modulates the mevalonate pathway decreasing cell migration and enhancing drug sensitivity in breast cancer cells.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
20 Dec 2023
20 Dec 2023
Historique:
received:
20
10
2023
accepted:
30
11
2023
revised:
09
11
2023
medline:
21
12
2023
pubmed:
21
12
2023
entrez:
20
12
2023
Statut:
epublish
Résumé
p140Cap is an adaptor protein involved in assembling multi-protein complexes regulating several cellular processes. p140Cap acts as a tumor suppressor in breast cancer (BC) and neuroblastoma patients, where its expression correlates with a better prognosis. The role of p140Cap in tumor metabolism remains largely unknown. Here we study the role of p140Cap in the modulation of the mevalonate (MVA) pathway in BC cells. The MVA pathway is responsible for the biosynthesis of cholesterol and non-sterol isoprenoids and is often deregulated in cancer. We found that both in vitro and in vivo, p140Cap cells and tumors show an increased flux through the MVA pathway by positively regulating the pace-maker enzyme of the MVA pathway, the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), via transcriptional and post-translational mechanisms. The higher cholesterol synthesis is paralleled with enhanced cholesterol efflux. Moreover, p140Cap promotes increased cholesterol localization in the plasma membrane and reduces lipid rafts-associated Rac1 signalling, impairing cell membrane fluidity and cell migration in a cholesterol-dependent manner. Finally, p140Cap BC cells exhibit decreased cell viability upon treatments with statins, alone or in combination with chemotherapeutic at low concentrations in a synergistic manner. Overall, our data highlight a new perspective point on tumor suppression in BC by establishing a previously uncharacterized role of the MVA pathway in p140Cap expressing tumors, thus paving the way to the use of p140Cap as a potent biomarker to stratify patients for better tuning therapeutic options.
Identifiants
pubmed: 38123597
doi: 10.1038/s41419-023-06357-z
pii: 10.1038/s41419-023-06357-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
849Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : IG 2022 - ID. 27353
Informations de copyright
© 2023. The Author(s).
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