title: Esculetin Induces Apoptosis Through EGFR/PI3K/Akt Signaling Pathway and Nucleophosmin Relocalization.
abstract: Esculetin, a coumarin compound, has anti-proliferative effects on various types of human cancer cells, but its effect on oral squamous cell carcinoma (OSCC) is unknown. In this study, we determined whether esculetin had anti-proliferative effects on two oral squamous cell lines, HN22, and HSC2. We found that esculetin inhibited cell viability by inducing apoptosis, as evinced by apoptotic cell morphologies, nuclear fragmentation, and the multi-caspase/MMP activity. Furthermore, proteomic analysis was used to identify the target-specific proteins involved in esculetin treatment. Intriguingly, apoptotic cell death by esculetin was associated with significant inhibition of the EGFR/PI3K/Akt signaling pathway. We also demonstrated that the expression of nucleophosmin (NPM) markedly decreased after esculetin treatment, and relocalization of NPM from the nucleous to the cytoplasm, together with p65, potentiated apoptotic stimulation. Additionally, our data indicated that NPM expression was markedly higher in OSCC tissues than in normal tissues. Our results collectively indicated that esculetin inhibited the proliferation of OSCC through EGFR-mediated signaling pathways and down-regulation of NPM as well as the perturbation of NPM trafficking from the nucleolus to the cytoplasm resulted in apoptosis.
authors.affiliation: Department of Dental Pharmacology, School of Dentistry, BK21 Plus, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: Department of Dental Pharmacology, School of Dentistry, BK21 Plus, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Jin Hyoung
authors.initials: JH
authors.lastname: Cho
authors.affiliation: Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, South Korea.
authors.forename: Seung-Yeop
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan, 614-052, Republic of Korea.
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.affiliation: Department of Oral and Maxillofacial Surgery, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Hongju
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Oral and Maxillofacial Surgery, Chonnam National University Hwasun Hospital, Hwasun, Jeonnam, Republic of Korea.
authors.forename: Seunggon
authors.initials: S
authors.lastname: Jung
authors.affiliation: Natural Medicine Research Institute, Department of Pharmacy, College of Pharmacy, Mokpo National University, Jeonnam, 534-729, Republic of Korea.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Shim
authors.affiliation: Department of Dental Pharmacology, School of Dentistry, BK21 Plus, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Jung-Il
authors.initials: JI
authors.lastname: Chae
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D000090243:Nucleophosmin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D040901:Proteomics / Q000379:methods; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014468:Umbelliferones / Q000494:pharmacology*
chemical_list: D066246:ErbB Receptors; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D014468:Umbelliferones; C000716967:NPM1 protein, human; C007628:esculetin
keywords: ESCULETIN; NPM; OSCC; PROTEOMICS