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Epithelial–mesenchymal transition of ovarian cancer cells is sustained by Rac1 through simultaneous activation of MEK1/2 and Src signaling pathways

Oncogene volume 36, pages 1546–1558 (2017)Cite this article

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Abstract

Epithelial–mesenchymal transition (EMT) is regarded as a crucial contributing factor to cancer progression. Diverse factors have been identified as potent EMT inducers in ovarian cancer. However, molecular mechanism sustaining EMT of ovarian cancer cells remains elusive. Here we show that the presence of SOS1/EPS8/ABI1 complex is critical for sustained EMT traits of ovarian cancer cells. Consistent with the role of SOS1/EPS8/ABI1 complex as a Rac1-specific guanine nucleotide exchange factor, depleting Rac1 results in the loss of most of mesenchymal traits in mesenchymal-like ovarian cancer cells, whereas expressing constitutively active Rac1 leads to EMT in epithelial-like ovarian cancer cells. With the aid of clinically tested inhibitors targeting various EMT-associated signaling pathways, we show that only combined treatment of mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) and Src inhibitors can abolish constitutively active Rac1-led EMT and mesenchymal traits displayed by mesenchymal-like ovarian cancer cells. Further experiments also reveal that EMT can be induced in epithelial-like ovarian cancer cells by co-expressing constitutively active MEK1 and Src rather than either alone. As the activities of Erk and Src are higher in ovarian cancer cells with constitutively active Rac1, we conclude that Rac1 sustains ovarian cancer cell EMT through simultaneous activation of MEK1/2 and Src signaling pathways. Importantly, we demonstrate that combined use of MEK1/2 and Src inhibitors effectively suppresses development of intraperitoneal xenografts and prolongs the survival of ovarian cancer-bearing mice. This study suggests that cocktail of MEK1/2 and Src inhibitors represents an effective therapeutic strategy against ovarian cancer progression.

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Acknowledgements

This work was supported by E-Institutes of Shanghai Municipal Education Commission (Project E03008), ‘085’ First-Class Discipline Construction Innovation Science and Technology Support Project of Shanghai University of TCM (085ZY1206), National Science Foundation of China (31229002), NIH CA 187152 and DoD OC120313 (W81XWH-13-1-0122).

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Authors and Affiliations

  1. Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    D Fang, W Wang, S-B Su & S Huang

  2. E-institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    D Fang, S-B Su & S Huang

  3. Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China

    H Chen

  4. Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, USA

    J Y Zhu & S Huang

  5. Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA

    Y Teng

  6. Georgia Cancer Center, Augusta University, Augusta, GA, USA

    Y Teng & H-F Ding

  7. Department of Cardiology, Changhai Hospital, Shanghai, China

    Q Jing

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Fang, D., Chen, H., Zhu, J. et al. Epithelial–mesenchymal transition of ovarian cancer cells is sustained by Rac1 through simultaneous activation of MEK1/2 and Src signaling pathways. Oncogene 36, 1546–1558 (2017). https://doi.org/10.1038/onc.2016.323

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