Mislocalized cytoplasmic p27 activates PAK1-mediated metastasis and is a prognostic factor in osteosarcoma.
Adolescent
Adult
Animals
Bone Neoplasms
/ diagnosis
Cell Line, Tumor
Cell Movement
Cyclin-Dependent Kinase Inhibitor p27
/ analysis
Cytoplasm
/ metabolism
Enzyme Activation
Female
Humans
Lung Neoplasms
/ metabolism
Male
Mice
Osteosarcoma
/ diagnosis
Prognosis
Protein Interaction Maps
Young Adult
p21-Activated Kinases
/ metabolism
PAK1
biomarkers
metastasis
osteosarcoma
p27
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
03
07
2019
revised:
19
11
2019
accepted:
18
12
2019
pubmed:
25
12
2019
medline:
2
2
2021
entrez:
25
12
2019
Statut:
ppublish
Résumé
The development of pulmonary metastasis is the leading cause of death in osteosarcoma (OS), which is the most common malignant bone tumor in children. We have previously reported that the tumor suppressor p27 (KIP1, CDKN1B) is frequently mislocalized to the cytoplasm of OS. However, its prognostic significance and metastatic mechanism are still elusive. Here, we show that cytoplasmic p27 significantly correlated with a higher metastatic status and poorer survival of OS patients (n = 136, P < 0.05), highlighting the clinical significance of p27 mislocalization in OS. Mechanistically, cytoplasmic p27 is co-immunoprecipitated with p21-activated kinase 1 (PAK1), which resulted in higher PAK1 phosphorylations, actin polymerization, and cell motility in p27-mislocalized OS cells. Silencing PAK1 expression in different p27-mislocalized OS cell lines decreased the migratory and adhesion abilities in vitro, as well as the development of pulmonary metastases in vivo. Similar PAK1-dependent motility was also observed in other p27-mislocalized cancer cell lines. In summary, our study suggests that cytoplasmic p27-mediated PAK1 activation is crucial for OS metastasis. A biomarker-guided targeted therapeutic approach for metastatic OS and other cancers harboring p27 mislocalization can be developed, where cytoplasmic p27 is used for risk stratification and PAK1 can be exploited as a potential therapeutic target.
Identifiants
pubmed: 31872963
doi: 10.1002/1878-0261.12624
pmc: PMC7138393
doi:
Substances chimiques
Cyclin-Dependent Kinase Inhibitor p27
147604-94-2
PAK1 protein, human
EC 2.7.11.1
Pak1 protein, mouse
EC 2.7.11.1
p21-Activated Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
846-864Subventions
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD074553
Pays : United States
Informations de copyright
© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
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