Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Tumor Biology

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. García-Sáez AJ. The secrets of the Bcl-2 family. Cell Death Differ. 2012;19:1733–40.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Yip KW, Reed JC. Bcl-2 family proteins and cancer. Oncogene. 2008;27:6398–406.

    Article  CAS  PubMed  Google Scholar 

  3. Delbridge AR, Strasser A. The BCL-2 protein family, BH3-mimetics and cancer therapy. Cell Death Differ. 2015;22:1071–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  23. Sato K. Cellular functions regulated by phosphorylation of EGFR on Tyr845. Int J Mol Sci. 2013;14:10761–90.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  25. Truong TH, Carroll KS. Redox regulation of epidermal growth factor receptor signaling through cysteine oxidation. Biochemistry. 2012;51:9954–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Herbst RS, Fukuoka M, Baselga J. Gefitinib--a novel targeted approach to treating cancer. Nat Rev Cancer. 2004;4:956–65.

    Article  CAS  PubMed  Google Scholar 

  30. da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol. 2011;6:49–69.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 

Download references

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

Author information

Authors and Affiliations

  1. Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Nowon-ro 75, Nowon-gu, Seoul, 139-706, Korea

    Eun Mi Kim, Jong Kuk Park, Sang-Gu Hwang & Hong-Duck Um

Authors
  1. Eun Mi Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jong Kuk Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sang-Gu Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong-Duck Um
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hong-Duck Um.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, E.M., Park, J.K., Hwang, SG. et al. Src and epidermal growth factor receptor mediate the pro-invasive activity of Bcl-w. Tumor Biol. 37, 1245–1252 (2016). https://doi.org/10.1007/s13277-015-3917-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3917-x

Keywords

Search

Navigation