title: Multifunctional effects of honokiol as an anti-inflammatory and anti-cancer drug in human oral squamous cancer cells and xenograft.
abstract: The aim of this study was to investigate anti-inflammatory and anti-cancer effects of honokiol (HK) in two oral squamous cancer cell carcinoma (OSCC) cell lines, HN22 and HSC4, through the regulation of inducible nitric oxide synthase (iNOS) and endoplasmic reticulum resident protein 44 (ERp44). Griess assay, zymography, and quantitative PCR were performed to study iNOS expression and subsequent nitric oxide (NO) production in OSCC cell lines. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic analysis was used to elucidate the proteins associated with ER stress and cellular cytotoxic response induced by HK. Pull-down assay and molecular modeling were performed to better understand how HK interacts with ERp44. In vitro and in vivo experiments in which ERp44 expression was knocked down were performed to better understand the effects of ERp44 on a cellular level and anti-cancer effects of HK. Expression levels of iNOS and subsequent NO secretion were reduced in OSCC cell lines treated with HK. ERp44 was significantly decreased in OSCC cell lines by HK treatment. HK directly bound to ERp44, and ERp44 knock-down significantly inhibited oral cancer cell proliferation and colony formation. Moreover, HK treatment effectively inhibited tumor growth and ERp44 levels in BALB/c nude mice bearing HN22 cell xenografts. Our findings suggest that HK inhibited inflammation and induced apoptosis by suppressing both iNOS/NO and ERp44 expression in HN22 and HSC4 cells and xenograft tumors, and thus could be a potent anti-inflammatory and anti-cancer drug candidate for human oral cancer treatment.
authors.affiliation: Department of Oral Pharmacology, School of Dentistry and Institute of Dental Bioscience, BK21 Plus, Chonbuk National University, Jeonju 651-756, 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 651-756, 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: Seon-Min
authors.initials: SM
authors.lastname: Park
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: 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, Chonnam National University Hwasun Hospital, Gwangju, Republic of Korea.
authors.forename: Seunggon
authors.initials: S
authors.lastname: Jung
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: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Joohyun
authors.initials: J
authors.lastname: Ryu
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Hanyong
authors.initials: H
authors.lastname: Chen
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan-gun, Jeonnam 534-729, Republic of Korea. Electronic address: s1004jh@gmail.com.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Shim
authors.affiliation: Department of Oral Pharmacology, School of Dentistry and Institute of Dental Bioscience, BK21 Plus, Chonbuk National University, Jeonju 651-756, Republic of Korea. Electronic address: jichae@jbnu.ac.kr.
authors.forename: Jung-Il
authors.initials: JI
authors.lastname: Chae
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002853:Chromatography, Liquid; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010084:Oxidation-Reduction; D053719:Tandem Mass Spectrometry; D023041:Xenograft Model Antitumor Assays; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D002118:Calcium; D017705:Lignans; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols
keywords: Apoptosis; Endoplasmic reticulum resident protein 44; Honokiol; Oral squamous cell carcinoma; Proteomics; Xenograft