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Tumor Biology

, Volume 37, Issue 1, pp 1245–1252 | Cite as

Src and epidermal growth factor receptor mediate the pro-invasive activity of Bcl-w

  • Eun Mi Kim
  • Jong Kuk Park
  • Sang-Gu Hwang
  • Hong-Duck Um
Original Article

Abstract

Members of the Bcl-2 family are established regulators of cell death. However, recent studies have shown that they can also regulate cell migration, invasion, and cancer metastasis. These functions of cancer cells are promoted by pro-survival Bcl-2 proteins (Bcl-2, Bcl-XL, and Bcl-w) but are suppressed by pro-apoptotic members (Bax and Bak). We have previously shown that Bcl-w and Bcl-XL enhance the ability of respiratory complex-I to produce reactive oxygen species (ROS), stimulating the phosphoinositide 3-kinase (PI3K)-dependent invasion pathway. Here, we show that Bcl-w overexpression increases the phosphorylation of epidermal growth factor receptor (EGFR) and Src, and their interaction. Our results show that ROS production induced by Bcl-w activates Src, which then binds to and phosphorylates EGFR, leading to stimulation of the PI3K-dependent invasion pathway. Importantly, Bcl-w-induced cell invasion was prevented by treating cells with gefitinib (Iressa, ZD1839), an anticancer drug that directly inhibits EGFR. We also show that Bcl-XL can stimulate Src and EGFR phosphorylation, and that this function of Bcl-XL and Bcl-w is antagonized by Bax and Bak. Overall, this study demonstrates the involvement of Src and EGFR in the regulation of cellular invasiveness by Bcl-2 proteins, suggesting that chemotherapeutics targeting EGFR may be useful in preventing the progression of cancers that have altered Bcl-2 protein functions.

Keywords

Bcl-2 family EGFR Src Cancer Cell invasion 

Notes

Acknowledgements

The authors thank Dr. Sang Won Kang (Ewha Woman’s University) for his comments during the initiation phase of this study. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (2012R1A2A2A01045978, 2012M2A2A7010422).

Conflicts of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Eun Mi Kim
    • 1
  • Jong Kuk Park
    • 1
  • Sang-Gu Hwang
    • 1
  • Hong-Duck Um
    • 1
  1. 1.Division of Radiation Cancer BiologyKorea Institute of Radiological and Medical SciencesSeoulKorea

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