title: Retinoic acid induces hypersegmentation and enhances cytotoxicity of neutrophils against cancer cells.
abstract: Hypersegmentation of nuclei is considered a distinct characteristic of the antitumoral phenotype of neutrophils. Retinoic acid, a metabolite of retinol, reorganizes and induces segmentation of the nucleus during the differentiation of neutrophils. However, the role of retinoic acid in the phenotype polarization of neutrophils has not been fully established. Here, we investigated the effect of retinoic acid on phenotype polarization of neutrophils. Retinoic acid-induced the hypersegmentation of human neutrophils via retinoic acid receptors and mTOR pathways. Retinoic acid-induced hypersegmented neutrophils enhanced neutrophil extracellular traps (NETs) formation in response to phorbol-12-myristate 13-acetate (PMA) and fMLP (N-Formylmethionine-leucyl-phenylalanine) stimulation, and increased cytotoxicity against various tumor cells. Moreover, retinoic acid treatment attenuated tumor growth in a murine model of tumor. Taken together, these results suggests that retinoic acid induces the phenotype polarization of neutrophils to exert antitumor effects.
authors.affiliation: Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea.
authors.forename: Sanjeeb
authors.initials: S
authors.lastname: Shrestha
authors.affiliation: Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea.
authors.forename: Shin-Yeong
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea.
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Yun
authors.affiliation: Department of Physiology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea.
authors.forename: Jun-Kyu
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Department of Biochemistry & Cell Biology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea.
authors.forename: Jae Man
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Microbiology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea.
authors.forename: Minsang
authors.initials: M
authors.lastname: Shin
authors.affiliation: Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea.
authors.forename: Dong-Keun
authors.initials: DK
authors.lastname: Song
authors.affiliation: Department of Physiology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea. Electronic address: cwhong@knu.ac.kr.
authors.forename: Chang-Won
authors.initials: CW
authors.lastname: Hong
mesh_terms: D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D065206:Extracellular Traps / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D007960:Leukocyte Disorders / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics
chemical_list: D017382:Reactive Oxygen Species; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D058570:TOR Serine-Threonine Kinases
keywords: Cytotoxicity; Neutrophils; Phenotype; Polarization; Retinoic acid