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Endocrine disrupting chemicals promote the growth of ovarian cancer cells via the ER-CXCL12-CXCR4 signaling axis.

ABSTRACT: The majority of ovarian cancers over-express the estrogen receptor (ER?) and grow in response to estrogens. We previously demonstrated that ER induction of the chemokine CXCL12 (stromal cell-derived factor-1) is required for estradiol (E2)-stimulated proliferation of human ovarian carcinoma cells. In the current study, we report that known "endocrine disrupting chemicals" (EDCs) display mitogenic activities in ovarian cancer cells via their ability to activate the ER and upregulate CXCL12 expression. Notably, the EDCs genistein, bisphenol A and HPTE stimulated both cell proliferation and induction of CXCL12 mRNA and protein in a manner comparable to estradiol. The effects were completely attenuated by the ER antagonist ICI 182,780, revealing that observed activities of these agents were receptor-mediated. In cell proliferation assays, the mitogenic effects of estradiol and EDCs were obviated by siRNAs targeting CXCL12 and restored upon addition of exogenous CXCL12. Furthermore, an inhibitor to the CXCL12 receptor CXCR4 completely attenuated growth-stimulatory effects of E2 and EDCs. These studies highlight a potential role of EDCs possessing estrogenic activities in the etiology of ovarian cancer. Moreover, they suggest that the ER-CXCL12-CXCR4 signaling axis may represent a promising target for development of therapeutics for ER+ ovarian cancers.

SUBMITTER: Hall JM

PROVIDER: S-EPMC4287997 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Endocrine disrupting chemicals promote the growth of ovarian cancer cells via the ER-CXCL12-CXCR4 signaling axis.

Hall Julie M JM Korach Kenneth S KS

Molecular carcinogenesis 20120430 9

The majority of ovarian cancers over-express the estrogen receptor (ERα) and grow in response to estrogens. We previously demonstrated that ER induction of the chemokine CXCL12 (stromal cell-derived factor-1) is required for estradiol (E2)-stimulated proliferation of human ovarian carcinoma cells. In the current study, we report that known "endocrine disrupting chemicals" (EDCs) display mitogenic activities in ovarian cancer cells via their ability to activate the ER and upregulate CXCL12 expres ...[more]

PMID: 22549810

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Project description:Introduction:Traditional chemotherapy for ovarian cancer is limited due to drug resistance and systemic side effects. Although various targeted drug delivery strategies have been designed to enhance drug accumulation at the tumor site, simply improvement of targeting capability has not consistently led to satisfactory outcomes. Herein, AMD3100 was selected as the targeting ligand because of its high affinity to chemokine receptor 4 (CXCR4), which was highly expressed on ovarian cancer cells. Moreover, the AMD3100 has been proved having blockage capability of stromal cell-derived factor 1 (SDF-1 or CXCL12)/CXCR4 axis and to be a sensitizer of chemotherapeutic therapy. We designed a dual-functional targeting delivery system by modifying paclitaxel (PTX)-loaded PEGylation bovine serum albumin (BSA) nanoparticles (NPs) with AMD3100 (AMD-NP-PTX), which can not only achieve specific tumor-targeting efficiency but also enhance the therapeutic outcomes. Methods:AMD3100 was chemically modified to Mal-PEG-NHS followed by reacting with BSA, then AMD-NP-PTX was synthesized and characterized. The targeting efficiency of AMD-NP was evaluated both in vitro and in vivo. The anticancer effect of AMD-NP-PTX was determined on Caov3 cells and ovarian cancer-bearing nude mice. Finally, the potential therapeutic mechanism was studied. Results:AMD-NP-PTX was synthesized successfully and well characterized. Cellular uptake assay and in vivo imaging experiments demonstrated that NPs could be internalized by Caov3 cells more efficiently after modification of AMD3100. Furthermore, the AMD-NP-PTX exhibited significantly enhanced inhibition effect on tumor growth and metastasis compared with PTX, NP-PTX and free AMD3100 plus NP-PTX both in vitro and in vivo, and demonstrated improved safety profile. We also confirmed that AMD-NP-PTX worked through targeting CXCL12/CXCR4 axis, thereby disturbing its downstream signaling pathways including epithelial-mesenchymal transition (EMT) processes and nuclear factor ?B (NF-?B) pathway. Conclusion:The AMD-NP-PTX we designed would open a new avenue for dual-functional NPs in ovarian cancer therapy.

Dataset Information

Endocrine disrupting chemicals promote the growth of ovarian cancer cells via the ER-CXCL12-CXCR4 signaling axis.

Publications

Endocrine disrupting chemicals promote the growth of ovarian cancer cells via the ER-CXCL12-CXCR4 signaling axis.

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