Epithelial-stromal communication via CXCL1-CXCR2 interaction stimulates growth of ovarian cancer cells through p38 activation.
Cell Communication
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Chemokine CXCL1
/ metabolism
Culture Media, Conditioned
/ pharmacology
Cytokines
/ pharmacology
Enzyme Activation
/ drug effects
Epithelial Cells
/ drug effects
Female
Fibroblasts
/ drug effects
Humans
MAP Kinase Signaling System
/ drug effects
Ovarian Neoplasms
/ enzymology
Phenylurea Compounds
/ pharmacology
Protein Binding
/ drug effects
Proto-Oncogene Proteins c-akt
/ metabolism
Receptors, Interleukin-8B
/ metabolism
Stromal Cells
/ drug effects
p38 Mitogen-Activated Protein Kinases
/ metabolism
CXCL1
CXCR2
Cell proliferation
Ovarian cancer
Ovarian fibroblast
Tumor microenvironment
p38 activation
Journal
Cellular oncology (Dordrecht)
ISSN: 2211-3436
Titre abrégé: Cell Oncol (Dordr)
Pays: Netherlands
ID NLM: 101552938
Informations de publication
Date de publication:
Feb 2021
Feb 2021
Historique:
accepted:
21
08
2020
pubmed:
11
9
2020
medline:
24
9
2021
entrez:
10
9
2020
Statut:
ppublish
Résumé
Paracrine interactions with the stromal environment, including fibroblasts, may be important in the pathogenesis of ovarian cancer. Here, we evaluated the effect of conditioned media derived from ovarian fibroblasts (fibroblast-CMs) and their major cytokines on the growth of ovarian cancer cells, as well as the involvement of mitogen-activated protein kinases (MAPKs) and AKT in mediating this effect. Ovarian cancer cells were cultured in serum-free media (SF), or conditioned media of fibroblasts derived from normal ovary (CM1) and ovarian tumor tissue (CM2). Cell proliferation was measured by MTT assay. Phosphorylation of MAPKs and AKT was evaluated by Western blotting. Specific inhibitors of MAPKs and AKT were used to evaluate their respective involvement in mediating increased cell growth. Cytokine levels in fibroblast-CMs were measured using Luminex assays. Immunohistochemical staining was conducted for CXCL1, CXCR2 and phosphorylated p38 in primary ovarian tumors. CM1 and CM2 significantly increased the growth of ovarian cancer cells relative to SF. In OVCAR3 and OVCAR4 cells, p38 phosphorylation was strongly induced by fibroblast-CMs, and pre-treatment with a p38 inhibitor prevented the growth increase induced by fibroblast-CMs. Fibroblasts secreted high levels of IL-6, IL-8, MCP1 and CXCL1. Treatment with only CXCL1 (1 μg/ml) increased cell growth and p38 phosphorylation. Treatment with a CXCR2 inhibitor effectively prevented p38 activation and cell growth induced by fibroblast-CMs. High expression of both CXCL1 and CXCR2 correlated with high expression of phosphorylated p38 in primary ovarian tumors. From our data, we conclude that CXCL1 is a key factor derived from ovarian fibroblasts that is responsible for increased ovarian cancer cell growth in part through p38 activation. Phosphorylated p38 can be used as a biomarker to predict CXCL1-CXCR2 interaction in vivo.
Identifiants
pubmed: 32910411
doi: 10.1007/s13402-020-00554-0
pii: 10.1007/s13402-020-00554-0
doi:
Substances chimiques
CXCL1 protein, human
0
CXCR2 protein, human
0
Chemokine CXCL1
0
Culture Media, Conditioned
0
Cytokines
0
Phenylurea Compounds
0
Receptors, Interleukin-8B
0
SB 225002
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
p38 Mitogen-Activated Protein Kinases
EC 2.7.11.24
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
77-92Subventions
Organisme : NCI NIH HHS
ID : P30 CA168524
Pays : United States
Organisme : National Research Foundation of Korea
ID : 2014R1A1A3050916
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