title: Immunogenicity of mammary tumor cells can be induced by shikonin via direct binding-interference with hnRNPA1.
abstract: Immunogenic cell death (ICD) of tumor cells occurs via various pathways that activate immune cell systems against cancer. Previous studies have demonstrated that shikonin (SK), a plant secondary metabolite, can confer strong pharmacological activities that activate ICD and strong immunogenicity of tumor cells. However, the exact hierarchical regulatory mechanisms including the molecular targets of SK-activated immunogenicity are still unknown. Here, the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was revealed to serve as a specific protein target for SK. This binding plays a key role in SK-stimulated ICD activity and the suppression of post-transcriptional mRNA processing, including nuclear export activity of newly synthesized mRNAs in mammary carcinoma cells in vitro. Moreover, it also mechanistically mediates the anti-metastatic effect of a tumor cell lysate (TCL) vaccine, which can be readily generated from SK-treated 4T1 tumor cells (SK-TCL), and the derived tumor-immunogenicity of SK-TCL-treated dendritic cells in vivo. Together, the identification of hnRNPA1 as the intracellular molecular target provides compelling pharmacology-based knowledge for the potential clinical use of SK-induced immunogenicity. In addition, SK may also serve as a potent suppressor that interferes with specific post-transcriptional activities, a mechanism which may be useful for exploitation in cancer therapeutics.
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Shu-Yi
authors.initials: SY
authors.lastname: Yin
authors.affiliation: Institute of Pharmacy and Biochemistry, University of Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Feng-Yin
authors.initials: FY
authors.lastname: Jian
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Yung-Hsiang
authors.initials: YH
authors.lastname: Chen
authors.affiliation: School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: Chia-I
authors.initials: CI
authors.lastname: Liu
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Andrew H J
authors.initials: AH
authors.lastname: Wang
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Yet-Ran
authors.initials: YR
authors.lastname: Chen
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsiao
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Ning-Sun
authors.initials: NS
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000627:therapeutic use*; D017209:Apoptosis / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1 / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D062105:Molecular Docking Simulation; D009285:Naphthoquinones / Q000276:immunology / Q000627:therapeutic use*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; C000619657:Hnrnpa1 protein, mouse; D009285:Naphthoquinones; D012333:RNA, Messenger; C000619656:hnRNPA1 protein, human; C016101:shikonin
keywords: heterogeneous nuclear ribonucleoprotein A1; immunogenic cell death; shikonin; tumor immunogenicity