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


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.


Bcl-2 family EGFR Src Cancer Cell invasion 



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



  1. 1.
    García-Sáez AJ. The secrets of the Bcl-2 family. Cell Death Differ. 2012;19:1733–40.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Yip KW, Reed JC. Bcl-2 family proteins and cancer. Oncogene. 2008;27:6398–406.CrossRefPubMedGoogle Scholar
  3. 3.
    Delbridge AR, Strasser A. The BCL-2 protein family, BH3-mimetics and cancer therapy. Cell Death Differ. 2015;22:1071–80.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Del Bufalo D, Biroccio A, Leonetti C, Zupi G. Bcl-2 overexpression enhances the metastatic potential of a human breast cancer line. FASEB J. 1997;11:947–53.PubMedGoogle Scholar
  5. 5.
    Choi J, Choi K, Benveniste EN, Rho SB, Hong YS, Lee JH, et al. Bcl-2 promotes invasion and lung metastasis by inducing matrix metalloproteinase-2. Cancer Res. 2005;65:5554–60.CrossRefPubMedGoogle Scholar
  6. 6.
    Zuo J, Ishikawa T, Boutros S, Xiao Z, Humtsoe JO, Kramer RH. Bcl-2 overexpression induces a partial epithelial to mesenchymal transition and promotes squamous carcinoma cell invasion and metastasis. Cancer Res. 2010;8:170–82.Google Scholar
  7. 7.
    Weiler M, Bähr O, Hohlweg U, Naumann U, Rieger J, Huang H, et al. BCL-xL: time-dependent dissociation between modulation of apoptosis and invasiveness in human malignant glioma cells. Cell Death Differ. 2006;13:1156–69.CrossRefPubMedGoogle Scholar
  8. 8.
    Du YC, Lewis BC, Hanahan D, Varmus H. Assessing tumor progression factors by somatic gene transfer into a mouse model: Bcl-xL promotes islet tumor cell invasion. PLoS Biol. 2007;5:2255–69.CrossRefGoogle Scholar
  9. 9.
    Ho JN, Kang GY, Lee SS, Kim J, Bae IH, Hwang SG, et al. Bcl-XL and STAT3 mediate malignant actions of gamma-irradiation in lung cancer cells. Cancer Sci. 2010;101:1417–23.CrossRefPubMedGoogle Scholar
  10. 10.
    Bae IH, Park MJ, Yoon SH, Kang SW, Lee SS, Choi KM, et al. Bcl-w promotes gastric cancer cell invasion by inducing matrix metalloproteinase-2 expression via phosphoinositide 3-kinase, Akt, and Sp1. Cancer Res. 2006;66:4991–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Bae IH, Yoon SH, Lee SB, Park JK, Ho JN, Um HD. Signaling components involved in Bcl-w-induced migration of gastric cancer cells. Cancer Lett. 2009;277:22–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Kim EM, Kim J, Park JK, Hwang SG, Kim WJ, Lee WJ, et al. Bcl-w promotes cell invasion by blocking the invasion-suppressing action of Bax. Cell Signal. 2012;24:1163–72.CrossRefPubMedGoogle Scholar
  13. 13.
    Kim EM, Park JK, Hwang SG, Kim WJ, Liu ZG, Kang SW, et al. Nuclear and cytoplasmic p53 suppress cell invasion by inhibiting respiratory complex-I activity via Bcl-2 family proteins. Oncotarget. 2014;5:8452–65.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lee HW, Lee SS, Lee SJ, Um HD. Bcl-w is expressed in a majority of infiltrative gastric adenocarcinomas and suppresses the cancer cell death by blocking stress-activated protein kinase/c-Jun NH2-terminal kinase activation. Cancer Res. 2003;63:1093–100.PubMedGoogle Scholar
  15. 15.
    Watanabe J, Kushihata F, Honda K, Sugita A, Tateishi N, Mominoki K, et al. Prognostic significance of Bcl-xL in human hepatocellular carcinoma. Surgery. 2004;135:604–12.CrossRefPubMedGoogle Scholar
  16. 16.
    Neri A, Marrelli D, Roviello F, DeMarco G, Mariani F, DeStefano A, et al. Bcl-2 expression correlates with lymphovascular invasion and long-term prognosis in breast cancer. Breast Cancer Res Treat. 2006;99:77–83.CrossRefPubMedGoogle Scholar
  17. 17.
    Keitel U, Scheel A, Thomale J, Halpape R, Kaulfuß S, Scheel C, et al. Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation. Oncotarget. 2014;5:11778–91.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Singh L, Pushker N, Saini N, Sen S, Sharma A, Bakhshi S, et al. Expression of pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins in human retinoblastoma. Clin Exp Ophthalmol. 2015;43:259–67.CrossRefPubMedGoogle Scholar
  19. 19.
    Brambilla E, Gazzeri S, Lantuejoul S, Coll JL, Moro D, Negoescu A, et al. p53 mutant immunophenotype and deregulation of p53 transcription pathway (Bcl2, Bax, and Waf1) in precursor bronchial lesions of lung cancer. Clin Cancer Res. 1998;4:1609–18.PubMedGoogle Scholar
  20. 20.
    Ogura E, Senzaki H, Yamamoto D, Yoshida R, Takada H, Hioki K, et al. Prognostic significance of Bcl-2, Bcl-xL/S, Bax and Bak expressions in colorectal carcinomas. Oncol Rep. 1999;6:365–9.PubMedGoogle Scholar
  21. 21.
    Coutinho-Camillo CM, Lourenço SV, Nishimoto IN, Kowalski LP, Soares FA. Expression of Bcl-2 family proteins and association with clinicopathological characteristics of oral squamous cell carcinoma. Histopathology. 2010;57:304–16.CrossRefPubMedGoogle Scholar
  22. 22.
    Yewale C, Baradia D, Vhora I, Patil S, Misra A. Epidermal growth factor receptor targeting in cancer: a review of trends and strategies. Biomaterials. 2013;34:8690–707.CrossRefPubMedGoogle Scholar
  23. 23.
    Sato K. Cellular functions regulated by phosphorylation of EGFR on Tyr845. Int J Mol Sci. 2013;14:10761–90.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Biscardi JS, Maa MC, Tice DA, Cox ME, Leu TH, Parsons SJ. c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function. J Biol Chem. 1999;274:8335–43.CrossRefPubMedGoogle Scholar
  25. 25.
    Truong TH, Carroll KS. Redox regulation of epidermal growth factor receptor signaling through cysteine oxidation. Biochemistry. 2012;51:9954–65.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Filosto S, Khan EM, Tognon E, Becker C, Ashfaq M, Ravid T, et al. EGF receptor exposed to oxidative stress acquires abnormal phosphorylation and aberrant activated conformation that impairs canonical dimerization. PLoS One. 2011;6:e23240.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lee BR, Um HD. Hydrogen peroxide suppresses U937 cell death by two different mechanisms depending on its concentration. Exp Cell Res. 1999;248:430–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Abe M, Kuroda Y, Hirose M, Watanabe Y, Nakano M, Handa T. Inhibition of autophosphorylation of epidermal growth factor receptor by small peptides in vitro. Br J Pharmacol. 2006;147:402–11.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Herbst RS, Fukuoka M, Baselga J. Gefitinib--a novel targeted approach to treating cancer. Nat Rev Cancer. 2004;4:956–65.CrossRefPubMedGoogle Scholar
  30. 30.
    da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol. 2011;6:49–69.CrossRefPubMedGoogle Scholar
  31. 31.
    Engelman JA, Mukohara T, Zejnullahu K, Lifshits E, Borrás AM, Gale CM, et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest. 2006;116:2695–706.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Tan AS, Baty JW, Berridge MV. The role of mitochondrial electron transport in tumorigenesis and metastasis. Biochim Biophys Acta. 1840;2014:1454–63.Google Scholar

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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