Endothelin causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells.
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 ETAreceptor (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.
Department of Health and Human Services, National Cancer Institute, Center for Cancer Research, Office of the Director, Bethesda, MD 20892, United States. Electronic address: moodyt@mail.nih.gov.
Terry W
TW
Moody
National Institutes of Health, National Institute of Diabetes, Digestive and Kidney Disease, Digestive Diseases Branch, Bethesda, MD 20892, United States.
Irene
I
Ramos-Alvarez
National Institutes of Health, National Institute of Diabetes, Digestive and Kidney Disease, Digestive Diseases Branch, Bethesda, MD 20892, United States.
Paula
P
Moreno
National Institutes of Health, National Institute of Diabetes, Digestive and Kidney Disease, Digestive Diseases Branch, Bethesda, MD 20892, United States.
Samuel A
SA
Mantey
National Cancer Institute, Cancer Inflammation Program, Frederick, MD 21702, United States.
Lisa
L
Ridnour
National Cancer Institute, Cancer Inflammation Program, Frederick, MD 21702, United States.
David
D
Wink
National Institutes of Health, National Institute of Diabetes, Digestive and Kidney Disease, Digestive Diseases Branch, Bethesda, MD 20892, United States.
Robert T
RT
Jensen
D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016232:Endothelins / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077341:Lapatinib; D010456:Peptides, Cyclic / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011759:Pyrrolidines / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D044022:Receptor, Endothelin A / Q000235:genetics; D044023:Receptor, Endothelin B / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects
D016232:Endothelins; D066246:ErbB Receptors; D000077156:Gefitinib; D000077341:Lapatinib; D010456:Peptides, Cyclic; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D011799:Quinazolines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D018719:Erb-b2 Receptor Tyrosine Kinases; C000588596:EDNRB protein, human; C511404:ZD4054; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C072247:cyclo(Trp-Asp-Pro-Val-Leu)
EGFR; Endothelin; HER2; Lung cancer; Transactivation