Epithelial-stromal communication via CXCL1-CXCR2 interaction stimulates growth of ovarian cancer cells through p38 activ
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ORIGINAL PAPER
Epithelial-stromal communication via CXCL1-CXCR2 interaction stimulates growth of ovarian cancer cells through p38 activation Geun-Young Park 1 & Harsh B. Pathak 2,3 & Andrew K. Godwin 2,3 & Youngjoo Kwon 1 Accepted: 21 August 2020 # International Society for Cellular Oncology 2020
Abstract Purpose 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. Methods 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. Results 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. Conclusions 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. Keywords Ovarian cancer . Tumor microenvironment . CXCL1 . CXCR2 . Cell proliferation . Ovarian fibroblast . p38 activation
1 Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13402-020-00554-0) contains supplementary material, which is available to authorized users. * Youngjoo Kwon [email protected] 1
Department of Food Science and Engineering, Ewha Womans University, 52, Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Republic of Korea
2
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
3
University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA
Ovarian cancer is a heterogeneous group of malignancies that affects the female reproductive organs. The
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