Immunogenicity of mammary tumor cells can be induced by shikonin via direct binding-interference with hnRNPA1

• Published in: Oncotarget 2016-07, Vol.7 (28), p.43629-43653
• Main Authors: Yin, Shu-Yi, Efferth, Thomas, Jian, Feng-Yin, Chen, Yung-Hsiang, Liu, Chia-I, Wang, Andrew H J, Chen, Yet-Ran, Hsiao, Pei-Wen, Yang, Ning-Sun
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - immunology; Antineoplastic Agents - therapeutic use; Apoptosis - immunology; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Cancer Vaccines - immunology; Cell Line, Tumor; Dendritic Cells - immunology; Female; Heterogeneous Nuclear Ribonucleoprotein A1 - immunology; Heterogeneous Nuclear Ribonucleoprotein A1 - metabolism; Humans; Mice; Mice, Inbred BALB C; Molecular Docking Simulation; Naphthoquinones - immunology; Naphthoquinones - therapeutic use; Research Paper; RNA Processing, Post-Transcriptional - drug effects; RNA, Messenger - metabolism; Tandem Mass Spectrometry; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.9660

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.