Epidermal growth factor signals regulate dihydropyrimidine dehydrogenase expression in EGFR-mutated non-small-cell lung cancer.
It has been shown that epidermal growth factor receptor (EGFR) mutation status is associated with 5-fluorouracil (5-FU) sensitivity in non-small-cell lung cancer (NSCLC). However, the relationship between EGFR mutation status and dihydropyrimidine dehydrogenase (DPD), a 5-FU degrading enzyme, is unknown.



We elucidated the crosstalk among the EGFR signal cascade, the DPD gene (DPYD), and DPD protein expression via the transcription factor Sp1 and the effect of EGFR mutation status on the crosstalk.



In the PC9 (exon19 E746-A750) study, EGF treatment induced up-regulation of both Sp1 and DPD; gefitinib, an EGFR-tyrosine kinase inhibitor (EGFR-TKI), and mithramycin A, a specific Sp-1 inhibitor, suppressed them. Among EGFR-mutated (PC9, HCC827; exon19 E746-A750 and H1975; exon21 L858R, T790M, gefitinib resistant) and -non-mutated (H1437, H1299) cell lines, EGF administration increased DPYD mRNA expression only in mutated cells (p < 0.05). Accordingly, gefitinib inhibited DPD protein expression only in PC9 and HCC827 cells, and mithramycin A inhibited it in EGFR-mutated cell lines, but not in wild-type. FU treatment decreased the level of cell viability more in gefitinib-treated EGFR-TKI sensitive cell lines. Further, combination treatment of FU and mithramycin A suppressed cell viability even in a gefitinib resistant cell line.



The EGFR signal cascade regulates DPD expression via Sp1 in EGFR mutant cells. These results might be a step towards new therapies targeting Sp1 and DPD in NSCLC with different EGFR mutant status.
Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Nagasaki, 852-8501, Japan.
Tetsuro
T
Tominaga
Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Nagasaki, 852-8501, Japan.
Tomoshi
T
Tsuchiya
Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Nagasaki, 852-8501, Japan.
Koji
K
Mochinaga
Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Nagasaki, 852-8501, Japan.
Junichi
J
Arai
Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Nagasaki, 852-8501, Japan.
Naoya
N
Yamasaki
Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Nagasaki, 852-8501, Japan.
Keitaro
K
Matsumoto
Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Nagasaki, 852-8501, Japan.
Takuro
T
Miyazaki
Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Nagasaki, 852-8501, Japan.
Toshiya
T
Nagasaki
Department of Surgery, Miyazaki University School of Medicine, 5200 Kihara, Miyazaki, Miyazaki, 889-1692, Japan.
Atsushi
A
Nanashima
Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Science, 1-14 Bunkyo, Nagasaki, Nagasaki, 852-8521, Japan.
Kazuhiro
K
Tsukamoto
Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Nagasaki, 852-8501, Japan. nagayasu@nagasaki-u.ac.jp.
Takeshi
T
Nagayasu
D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics*; D005472:Fluorouracil / Q000494:pharmacology; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D009154:Mutation; D008926:Plicamycin / Q000031:analogs & derivatives / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism*
D011799:Quinazolines; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D004815:Epidermal Growth Factor; C066851:mithramycin A; D042943:Dihydrouracil Dehydrogenase (NADP); C512478:EGFR protein, human; D066246:ErbB Receptors; D008926:Plicamycin; D000077156:Gefitinib; D005472:Fluorouracil
5-fluorouracil; Dihydropyrimidine dehydrogenase; Epidermal growth factor receptor mutation; Non-small-cell lung cancer; Sp1