Li-Chuan Chung1, Kun-Chun Chiang2, Tsui-Hsia Feng3, Kang-Shuo Chang4, Sung-Ting Chuang4, Yu-Jen Chen5, Ke-Hung Tsui6, Jehn-Chuan Lee7,8, Horng-Heng Juang4,6. 1. Department of General Education Center, Mackay Medicine, Nursing and Management College, New Taipei City, Taiwan. 2. Zebrafish Center, Department of General Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan. 3. School of Nursing, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan. 4. Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan. 5. Department of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan. 6. Department of Urology, Chang Gung Memorial Hospital-Linkou, Kwei-Shan, Tao-Yuan, Taiwan. 7. Department of Otolaryngology, Mackay Memorial Hospital, Taipei, Taiwan. 8. School of Medicine, Mackay Medical College, New Taipei City, Taiwan.
Abstract
SCOPE: 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. METHODS AND RESULTS: 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. CONCLUSION: CAPE activated MAPK signaling pathway and increased NDRG1 expression through phosphorylation of ERK1/2 to repress OSCC cells growth.
SCOPE: 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. METHODS AND RESULTS: 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. CONCLUSION:CAPE activated MAPK signaling pathway and increased NDRG1 expression through phosphorylation of ERK1/2 to repress OSCC cells growth.