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Cisplatin targets the stromal cell-derived factor-1-CXC chemokine receptor type 4 axis to suppress metastasis and invasion of ovarian cancer-initiating cells

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Tumor Biology

Abstract

In ovarian cancer, CD44+/CD117+ stem cells, also known as cancer-initiating cells (CICs), are highly proliferative and invasive. Therefore, the CD44+/CD117+ subpopulation is thought to be an important target for novel therapeutic strategies. In this study, we investigated the effects of cisplatin (CDDP) on metastasis and invasion suppression of ovarian CICs by targeting the CXC chemokine receptor-4 (CXCR4) signaling pathway in vitro and in vivo. CD44+/CD117+ ovarian CICs were enriched from human primary ovarian tumor tissues and confirmed by flow cytometry sorting. A 3-(4,5-dimethylthiazol-2-yl)-2.5-dipheny-tetrazolium bromide (MTT) assay revealed significant inhibition of proliferation of ovarian CICs with increasing CDDP drug concentrations. Moreover, colony formation and transwell migration assays indicated that CDDP significantly suppressed the invasive capacity of ovarian CICs in vitro. The expression levels of stromal cell-derived factor (SDF)-1, CXCR4, matrix metalloproteinase (MMP) 2, and MMP9 mRNA and protein levels were significantly reduced in CDDP-treated cells compared to untreated ovarian CICs. Furthermore, xenograft experiments confirmed that CDDP suppressed the growth of xenograft tumors formed by ovarian CICs in vivo. In addition, CXCR4 agonist (diprotin A) treatment of ovarian CICs weakened the effects of CDDP and enhanced SDF-1-CXCR4 axis expression in ovarian CICs. Thus, the SDF-1-CXCR4 axis is an important mediator of proliferation and invasion in CXCR4-overexpressing ovarian cancer-initiating cells (OCICs). Furthermore, CDDP inhibits invasion and metastasis of OCICs by targeting SDF-1-CXCR4 axis expression.

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Acknowledgments

This work was supported by a grant from the National Natural Science Foundation of China (no. 81202811) and the Shanghai Municipal Health Bureau Fund (no. 20124320) to Te Liu.

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Authors and Affiliations

  1. Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200031, China

    Zhi-hua Yu & Te Liu

  2. International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University, Shanghai, 200030, China

    Te Liu & Yong-tao Gao

  3. Department of Oral and Craniofacial Science, Ninth People’s Hospital, College of Stomatology and Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yan-hui Zhao

  4. School of Life Science and Technology, Tongji University, Shanghai, 200092, China

    Yong-yi Huang

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  1. Zhi-hua Yu
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  2. Te Liu
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  3. Yan-hui Zhao
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  4. Yong-yi Huang
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  5. Yong-tao Gao
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Correspondence to Yong-tao Gao.

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Zhi-hua Yu, Te Liu, and Yan-hui Zhao contributed equally to this work.

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Yu, Zh., Liu, T., Zhao, Yh. et al. Cisplatin targets the stromal cell-derived factor-1-CXC chemokine receptor type 4 axis to suppress metastasis and invasion of ovarian cancer-initiating cells. Tumor Biol. 35, 4637–4644 (2014). https://doi.org/10.1007/s13277-014-1607-8

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  • DOI: https://doi.org/10.1007/s13277-014-1607-8

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