Endothelin causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells
•ET-1 addition to NSCLC cells causes tyrosine phosphorylation of the EGFR, HER2 and ERK.•ET-1 binds with high affinity to NSCLC and causes elevated cytosolic Ca2+ which is blocked by the ETAR antagonists BQ123 and ZD4054.•The ability of ET-1 to cause EGFR and HER2 transactivation is blocked by ETAR...
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Veröffentlicht in: | Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2017-04, Vol.90, p.90-99 |
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Sprache: | eng |
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Zusammenfassung: | •ET-1 addition to NSCLC cells causes tyrosine phosphorylation of the EGFR, HER2 and ERK.•ET-1 binds with high affinity to NSCLC and causes elevated cytosolic Ca2+ which is blocked by the ETAR antagonists BQ123 and ZD4054.•The ability of ET-1 to cause EGFR and HER2 transactivation is blocked by ETAR antagonists and gefitinib, a tyrosine kinase inhibitor.•ET-1 stimulates the growth of NSCLC cells, whereas ETAR antagonists and gefitinib inhibit NSCLC proliferation.
Endothelin (ET)-1 is an important peptide in cancer progression stimulating cellular proliferation, tumor angiogenesis and metastasis. ET-1 binds with high affinity to the ETA receptor (R) and ETBR on cancer cells. High levels of tumor ET-1 and ETAR are associated with poor survival of lung cancer patients. Here the effects of ET-1 on epidermal growth factor (EGF)R and HER2 transactivation were investigated using non-small cell lung cancer (NSCLC) cells. ETAR mRNA was present in all 10 NSCLC cell lines examined. Addition of ET-1 to NCI-H838 or H1975 cells increased EGFR, HER2 and ERK tyrosine phosphorylation within 2min. The increase in EGFR and HER2 transactivation caused by ET-1 addition to NSCLC cells was inhibited by lapatinib (EGFR and HER2 tyrosine kinase inhibitor (TKI)), gefitinib (EGFR TKI), ZD4054 or BQ-123 (ETAR antagonist), GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor) or Tiron (superoxide scavenger). ET-1 addition to NSCLC cells increased cytosolic Ca2+ and reactive oxygen species. ET-1 increased NSCLC clonal growth, whereas BQ123, ZD4054, lapatinib or gefitinib inhibited proliferation. The results indicate that ET-1 may regulate NSCLC cellular proliferation in an EGFR- and HER2-dependent manner. |
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ISSN: | 0196-9781 1873-5169 |
DOI: | 10.1016/j.peptides.2017.01.012 |