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Effects of silibinin on growth and invasive properties of human ovarian carcinoma cells through suppression of heregulin/HER3 pathway

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Tumor Biology

Abstract

Epithelial ovarian cancer (EOC) is the most fatal gynecological malignancy due to its high proliferative and invasive capacities. A heregulin (HRG)/HER3 autocrine loop increases proliferative and metastatic properties of EOC cells, suggesting that modulators of this signaling pathway may prove effective to trammel growth and motility of these cells. This study aimed to evaluate the effects of multi-tyrosine kinase inhibitor silibinin on proliferative and invasive characteristics of EOC cell lines OVCAR8 and SKOV3 through suppression of the HRG/HER3 pathway. To achieve this, the effects of silibinin on proliferation, DNA synthesis, clonogenicity, cell cycle progression, cathepsin B enzymatic activity, and migration and invasion were explored in vitro. Silibinin suppressed proliferation, DNA synthesis, and clonogenic abilities of OVCAR8 and SKOV3 cells through inhibition of the autocrine HRG/HER3 circuit. Silibinin-mediated attenuation of the HER3 signaling disabled the HER3/AKT/survivin axis and thereby, induced G1/S cell cycle arrest. Furthermore, silibinin reduced invasive potentials of the EOC cells through quelling the HRG/HER3 pathway and suppression of cathepsin B activity. Altogether, these results suggest that silibinin is a potential anti-cancer drug to inhibit proliferative and invasive characteristics of the EOC cells that exhibit an autocrine HRG/HER3 pathway.

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Authors and Affiliations

  1. Hematology/Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Majid Momeny, Ghazaleh Zarrinrad, Sepehr Javadikooshesh, Marjan Yaghmaie, Kamran Alimoghaddam, Ardeshir Ghavamzadeh & Seyed H. Ghaffari

  2. Department of Surgery, Division of Cardiothoracic Surgery, Washington University in St. Louis, Saint Louis, MO, USA

    Reza Ghasemi

  3. Department of Cancer Research, Max Delbrueck Center for Molecular Medicine, Berlin, Germany

    Giovanni Valenti

  4. QIMR Berghofer Medical Research Institute, Queensland, Australia

    Mariska Miranda

  5. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Ali Zekri & Sepehr Javadikooshesh

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  1. Majid Momeny
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  2. Reza Ghasemi
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  4. Mariska Miranda
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Fig. S1

Effects of HER2 and HER3-targeted therapies on proliferation of EOC cells. A BrdU proliferation assay was conducted to investigate the anti-proliferative effects of trastuzumab (20 μg/mL) and H3.105.5 (20 μg/mL) on OVCAR8 and SKOV3 cells over 72 h of treatment. Data are given as mean ± SD. Statistically significant values of *p < 0.05, **p < 0.01 and, ***p < 0.001 were determined compared with the control. (JPEG 32 kb)

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Momeny, M., Ghasemi, R., Valenti, G. et al. Effects of silibinin on growth and invasive properties of human ovarian carcinoma cells through suppression of heregulin/HER3 pathway. Tumor Biol. 37, 3913–3923 (2016). https://doi.org/10.1007/s13277-015-4220-6

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  • DOI: https://doi.org/10.1007/s13277-015-4220-6

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