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

// Shu-Yi Yin 1 , Thomas Efferth 2 , Feng-Yin Jian 1 , Yung-Hsiang Chen 1 , Chia-I Liu 3 , Andrew H.J. Wang 4 , Yet-Ran Chen 1 , Pei-Wen Hsiao 1 and Ning-Sun Yang 1 1 Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC 2 Institute of Pharmacy and Biochemistry, University of Mainz, Germany 3 School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan, ROC 4 Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, ROC Correspondence to: Ning-Sun Yang, email: nsyang@gate.sinica.edu.tw Keywords: shikonin, heterogeneous nuclear ribonucleoprotein A1, tumor immunogenicity, immunogenic cell death Received: October 01, 2015      Accepted: May 13, 2016      Published: August 14, 2018 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.