Plasminogen Activator Inhibitor 1 (PAI1) Promotes Actin Cytoskeleton Reorganization and Glycolytic Metabolism in Triple-Negative Breast Cancer.
Actin Cytoskeleton
/ metabolism
Animals
Cell Line, Tumor
Cell Movement
Female
Gene Expression Profiling
/ methods
Gene Expression Regulation, Neoplastic
Glycolysis
High-Throughput Nucleotide Sequencing
Humans
Lung Neoplasms
/ genetics
MAP Kinase Signaling System
Mice
Neoplasm Transplantation
Plasminogen Activator Inhibitor 1
/ genetics
Triple Negative Breast Neoplasms
/ genetics
Up-Regulation
Whole Genome Sequencing
Journal
Molecular cancer research : MCR
ISSN: 1557-3125
Titre abrégé: Mol Cancer Res
Pays: United States
ID NLM: 101150042
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
07
08
2018
revised:
22
10
2018
accepted:
29
01
2019
pubmed:
6
2
2019
medline:
29
4
2020
entrez:
6
2
2019
Statut:
ppublish
Résumé
Migration and invasion of cancer cells constitute fundamental processes in tumor progression and metastasis. Migratory cancer cells commonly upregulate expression of plasminogen activator inhibitor 1 (PAI1), and PAI1 correlates with poor prognosis in breast cancer. However, mechanisms by which PAI1 promotes migration of cancer cells remain incompletely defined. Here we show that increased PAI1 drives rearrangement of the actin cytoskeleton, mitochondrial fragmentation, and glycolytic metabolism in triple-negative breast cancer (TNBC) cells. In two-dimensional environments, both stable expression of PAI1 and treatment with recombinant PAI1 increased migration, which could be blocked with the specific inhibitor tiplaxtinin. PAI1 also promoted invasion into the extracellular matrix from coculture spheroids with human mammary fibroblasts in fibrin gels. Elevated cellular PAI1 enhanced cytoskeletal features associated with migration, actin-rich migratory structures, and reduced actin stress fibers. In orthotopic tumor xenografts, we discovered that TNBC cells with elevated PAI1 show collagen fibers aligned perpendicular to the tumor margin, an established marker of invasive breast tumors. Further studies revealed that PAI1 activates ERK signaling, a central regulator of motility, and promotes mitochondrial fragmentation. Consistent with known effects of mitochondrial fragmentation on metabolism, fluorescence lifetime imaging microscopy of endogenous NADH showed that PAI1 promotes glycolysis in cell-based assays, orthotopic tumor xenografts, and lung metastases. Together, these data demonstrate for the first time that PAI1 regulates cancer cell metabolism and suggest targeting metabolism to block motility and tumor progression. IMPLICATIONS: We identified a novel mechanism through which cancer cells alter their metabolism to promote tumor progression.
Identifiants
pubmed: 30718260
pii: 1541-7786.MCR-18-0836
doi: 10.1158/1541-7786.MCR-18-0836
pmc: PMC6497540
mid: NIHMS1520803
doi:
Substances chimiques
Plasminogen Activator Inhibitor 1
0
SERPINE1 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1142-1154Subventions
Organisme : NCI NIH HHS
ID : R50 CA221807
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA195655
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA210152
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA222563
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA196018
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
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