Caffeic acid phenethyl ester upregulates N-myc downstream regulated gene 1 via ERK pathway to inhibit human oral cancer cell growth in vitro and in vivo.
Caffeic acid phenethyl ester (CAPE), a bioactive component of propolis, is considered as a new anti-cancer agent. Oral squamous cell carcinoma (OSCC) is the most common oral cancer with unsatisfying survival. N-myc downstream regulated family genes (NDRGs) involve in numerous physiological processes. We investigated the anti-cancer effect of CAPE on OSCC and related mechanisms.



Cell proliferation assay, western blot, gene transfection and knockdown, and reporter assay were applied. We showed that CAPE attenuated OSCC cell proliferation and invasion in vitro, and safely and effectively inhibited OSCC cell growth in a xenograft animal model. CAPE treatment induced NDRG1, but not NDRG2 and NDRG3, expression in OSCC cells as determined by western blot, RT-qPCR, and reporter assay. The 5'-deletion assay demonstrated that CAPE increased NDRG1 promoter activity depending on the region of -128 to +46 of the 5'-flanking of NDRG1 gene. NDRG1 gene knockdown attenuated CAPE anti-growth effect on OSCC cells. CAPE activated mitogen-activated protein kinase (MAPK) signaling pathway. The extracellular signal regulated kinase (ERK) inhibitor (PD0325901) and ERK1 knockdown blocked CAPE-induced NDRG1 expression in OSCC cells.



CAPE activated MAPK signaling pathway and increased NDRG1 expression through phosphorylation of ERK1/2 to repress OSCC cells growth.
Department of General Education Center, Mackay Medicine, Nursing and Management College, New Taipei City, Taiwan.
Li-Chuan
LC
Chung
Zebrafish Center, Department of General Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan.
Kun-Chun
KC
Chiang
School of Nursing, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan.
Tsui-Hsia
TH
Feng
Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan.
Kang-Shuo
KS
Chang
Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan.
Sung-Ting
ST
Chuang
Department of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan.
Yu-Jen
YJ
Chen
Department of Urology, Chang Gung Memorial Hospital-Linkou, Kwei-Shan, Tao-Yuan, Taiwan.
Ke-Hung
KH
Tsui
Department of Otolaryngology, Mackay Memorial Hospital, Taipei, Taiwan.|School of Medicine, Mackay Medical College, New Taipei City, Taiwan.
Jehn-Chuan
JC
Lee
Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan.|Department of Urology, Chang Gung Memorial Hospital-Linkou, Kwei-Shan, Tao-Yuan, Taiwan.
Horng-Heng
HH
Juang
D000818:Animals; D002109:Caffeic Acids / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D000077195:Squamous Cell Carcinoma of Head and Neck; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D002109:Caffeic Acids; D018797:Cell Cycle Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D047908:Intracellular Signaling Peptides and Proteins; D010626:Phenylethyl Alcohol; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C055494:caffeic acid phenethyl ester
CAPE; MAPK; NDRG1; OECM-1; Oral cancer; SAS