2. Academic Validation
  3. PAC1 regulates receptor tyrosine kinase transactivation in a reactive oxygen species-dependent manner

PAC1 regulates receptor tyrosine kinase transactivation in a reactive oxygen species-dependent manner

  • Peptides. 2019 Oct;120:170017. doi: 10.1016/j.peptides.2018.09.005.
Terry W Moody 1,  Lingaku Lee 2,  Tatiana Iordanskaia 2,  Irene Ramos-Alvarez 2,  Paola Moreno 2,  Howard E Boudreau 3,  Thomas L Leto 3,  Robert T Jensen 2
Affiliations

Affiliations

  • 1 Department of Health and Human Services, National Institutes of Health, National Cancer Institute, Center for Cancer Research, 9609 Medical Center Drive, Room 2W-340, Bethesda, MD, 20892, USA. Electronic address: moodyt@mail.nih.gov.
  • 2 National Institute of Diabetes, Digestive and Kidney Disease, Digestive Diseases Branch, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
  • 3 National Institute of Allergy and Infectious Diseases, Lab. Host Defenses, 12441 Parklawn Dr., Rockville, MD, 20852, USA.
PMID: 30273693 DOI: 10.1016/j.peptides.2018.09.005
Abstract

Pituitary Adenylate Cyclase activating polypeptide (PACAP) is a growth factor for lung Cancer cells. PACAP-27 or PACAP-38 binds with high affinity to non-small cell lung Cancer (NSCLC) cells, causing elevated cytosolic CA2+, increased proliferation and increased phosphorylation of extracellular regulated kinase (ERK) and the epidermal growth factor receptor (EGFR). The role of Reactive Oxygen Species (ROS) was investigated in these processes. Addition of PACAP-38 to NCI-H838 or A549 cells increased the tyrosine phosphorylation of the EGFR, HER2 and ERK significantly by 4-, 3-, and 2-fold, respectively. The transactivation of the EGFR and HER2 was inhibited by gefitinib or lapatinib (tyrosine kinase inhibitors), PACAP (6-38) (PAC1 antagonist), N-acetylcysteine (NAC is an anti-oxidant) or dipheyleneiodonium (DPI is an inhibitor of Nox and Duox Enzymes). PACAP-38 addition to NSCLC cells increased ROS which was inhibited by PACAP (6-38), NAC or DPI. NOX1, NOX2, Nox3, NOX4, Nox5, Duox1 and Duox2 mRNA was present in many NSCLC cell lines. PACAP-38 stimulated the growth of NSCLC cells whereas PACAP (6-38), gefitinib or DPI inhibited proliferation. The results show that ROS are essential for PAC1 to regulate EGFR and HER2 transactivation as well as proliferation of NSCLC cells.

Keywords

Duox; EGFR; ERK; HER2; Lung cancer; Nox; PAC1; ROS; Transactivation.

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