title: Role of transcription factor Sp1 in the 4-O-methylhonokiol-mediated apoptotic effect on oral squamous cancer cells and xenograft.
abstract: Recently, biphenolic components derived from the Magnolia family have been studied for anti-cancer, anti-stress, and anti-inflammatory pharmacological effects. However, the pharmacological mechanism of action of 4-O-methylhonokiol (MH) is not clear in oral cancer. The aim of this study was to investigate the role of MH in apoptosis and its molecular mechanism in oral squamous cell carcinoma (OSCC) cell lines, HN22 and HSC4, as well as tumor xenografts. Here, we demonstrated that MH decreased cell growth and induced apoptosis in HN22 and HSC4 cells through the regulation of specificity protein 1 (Sp1). We employed several experimental techniques such as MTS assay, DAPI staining, PI staining, Annexin-V/7-ADD staining, RT-PCR, western blot analysis, immunocytochemistry, immunohistochemistry, TUNEL assay and in vivo xenograft model analysis. MH inhibited Sp1 protein expression and reduced Sp1 protein levels via both proteasome-dependent protein degradation and inhibition of protein synthesis in HN22 and HSC4 cells; MH did not alter Sp1 mRNA levels. We found that MH directly binds Sp1 by Sepharose 4B pull-down assay and molecular modeling. In addition, treatment with MH or knocking down Sp1 expression suppressed oral cancer cell colony formation. Moreover, MH treatment effectively inhibited tumor growth and Sp1 levels in BALB/c nude mice bearing HN22 cell xenografts. These results indicated that MH inhibited cell growth, colony formation and also induced apoptosis via Sp1 suppression in OSCC cells and xenograft tumors. Thus, MH is a potent anti-cancer drug candidate for oral cancer.
authors.affiliation: Department of Oral Pharmacology, School of Dentistry and Institute of Dental Bioscience, BK21 plus, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Jin Hyoung
authors.initials: JH
authors.lastname: Cho
authors.affiliation: Department of Oral Pharmacology, School of Dentistry and Institute of Dental Bioscience, BK21 plus, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Ra Ham
authors.initials: RH
authors.lastname: Lee
authors.affiliation: Department of Oral Pharmacology, School of Dentistry and Institute of Dental Bioscience, BK21 plus, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: Pohang Center for Evaluation of Biomaterials, Pohang, Gyeongbuk, Republic of Korea.
authors.forename: Jae-Cheon
authors.initials: JC
authors.lastname: Shin
authors.affiliation: Pohang Center for Evaluation of Biomaterials, Pohang, Gyeongbuk, Republic of Korea.
authors.forename: Seon-Min
authors.initials: SM
authors.lastname: Park
authors.affiliation: Department of Animal Science, College of Agricultural and Life Science, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Nag-Jin
authors.initials: NJ
authors.lastname: Choi
authors.affiliation: Department of Animal Science and Technology, Sunchon National University, Suncheon, Republic of Korea.
authors.forename: Kang Seok
authors.initials: KS
authors.lastname: Seo
authors.affiliation: Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan-gun, Republic of Korea.
authors.forename: Goo
authors.initials: G
authors.lastname: Yoon
authors.affiliation: Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan-gun, Republic of Korea.
authors.forename: Seung-Sik
authors.initials: SS
authors.lastname: Cho
authors.affiliation: Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan-gun, Republic of Korea.
authors.forename: Ka Hwi
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan-gun, Republic of Korea.
authors.forename: Jung Jae
authors.initials: JJ
authors.lastname: Cho
authors.affiliation: Department of Pharmacy, Keimyung University, Daegu, Republic of Korea.
authors.forename: Young Sik
authors.initials: YS
authors.lastname: Cho
authors.affiliation: College of Pharmacy, Medical Research Center, Chungbuk National University, Cheongju, Republic of Korea.
authors.forename: Dae Hwan
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Oral Biochemistry, Dental Science Research Institute and the BK21 Project, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
authors.affiliation: Department of Oral Biochemistry, Dental Science Research Institute and the BK21 Project, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Lee
authors.affiliation: Department of Oral and Maxillofacial Surgery, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Hong Ju
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Department of Oral and Maxillofacial Surgery, Chonnam National University Hwasun Hospital, Gwangju, Republic of Korea.
authors.forename: Seunggon
authors.initials: S
authors.lastname: Jung
authors.affiliation: Department of Prosthodontics, School of Dentistry, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Jae-Min
authors.initials: JM
authors.lastname: Seo
authors.affiliation: Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Hanyong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Oral Pharmacology, School of Dentistry and Institute of Dental Bioscience, BK21 plus, Chonbuk National University, Jeonju, Republic of Korea. Electronic address: jichae@jbnu.ac.kr.
authors.forename: Jung-Il
authors.initials: JI
authors.lastname: Chae
authors.affiliation: Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan-gun, Republic of Korea. Electronic address: s1004jh@gmail.com.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Shim
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D017705:Lignans / Q000494:pharmacology*; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000473:pathology; D009368:Neoplasm Transplantation; D016329:Sp1 Transcription Factor / Q000502:physiology*
chemical_list: C542058:4-O-methylhonokiol; D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D017705:Lignans; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human
keywords: 4-O-methylhonokiol; Apoptosis; Oral squamous cell carcinoma; Specificity protein 1; Xenograft