Gefitinib inhibits MUC5AC synthesis in mucin-secreting non-small cell lung cancer cells.
Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is an active agent in non-small cell lung cancer, and rapidly relieves bronchorrhea in patients with bronchioloalveolar carcinoma before the improvement of radiological findings. In addition, epidermal growth factor regulates mucin secretion in normal airway goblet cells. The present study was designed to clarify whether gefitinib modifies mucin production in lung cancer cell lines apart from its anti-proliferative effects, using A549 adenocarcinoma and NCI-H292 mucoepidermoid carcinoma cells expressing EGFR and MUC5AC mRNA. Mucin synthesis was measured by RT-PCR and ELISA, and MAPK and Akt, the downstream targets of EGFR, were examined by Western blotting assay. The clinically-achievable concentration of 1muM gefitinib inhibited the growth of both cells by only 10%, but gefitinib suppressed MUC5AC mRNA levels subsequent to a decrease in intracellular and secreted MUC5AC protein. Gefitinib also inhibited the phosphorylation of MAPK and Akt, and the selective inhibitors PD98059 and LY294002 also suppressed MUC5AC protein synthesis. These findings suggest that gefitinib may inhibits MUC5AC synthesis, at least in part, through MAPK and Akt signaling pathways. Thus, gefitinib inhibits mucin production, which is encouraging for trials involving its use against bronchorrhea in patients with lung cancer.
Kitazaki
Takeshi
T
Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. tkita@ma.ejnet.ne.jp
Soda
Hiroshi
H
Doi
Seiji
S
Nakano
Hirohumi
H
Nakamura
Yoichi
Y
Kohno
Shigeru
S
D000230:Adenocarcinoma / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D055271:Mucin 5AC; D009077:Mucins / Q000096:biosynthesis*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D009077:Mucins; D011799:Quinazolines; D051058:Oncogene Protein v-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D000077156:Gefitinib