Immunogenicity of mammary tumor cells can be induced by shikonin via direct binding-interference with hnRNPA1
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Shu-Yi Yin1, Thomas Efferth2, Feng-Yin Jian1, Yung-Hsiang Chen1, Chia-I Liu3, Andrew H.J. Wang4, Yet-Ran Chen1, Pei-Wen Hsiao1 and Ning-Sun Yang1
1Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC
2Institute of Pharmacy and Biochemistry, University of Mainz, Germany
3School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan, ROC
4Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, ROC
Ning-Sun Yang, email: [email protected]
Keywords: shikonin, heterogeneous nuclear ribonucleoprotein A1, tumor immunogenicity, immunogenic cell death
Received: October 01, 2015 Accepted: May 13, 2016 Published: August 14, 2018
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.
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