TY - JOUR
T1 - Immunogenicity of mammary tumor cells can be induced by shikonin via direct binding-interference with hnRNPA1
AU - Yin, Shu Yi
AU - Efferth, Thomas
AU - Jian, Feng Yin
AU - Chen, Yung Hsiang
AU - Liu, Chia-I
AU - Wang, Andrew H.J.
AU - Chen, Yet Ran
AU - Hsiao, Pei Wen
AU - Yang, Ning Sun
N1 - Funding Information:
This work was supported by grants from the National Science Council (NSC 102-2320-B-001-003) and an institutional research grant from Academia Sinica, Taiwan (99-Academia Sinica Investigator Award-12). We thank the Laboratory Animal Core Facility in the Agricultural Biotechnology Research Center of Academia Sinica for assistance in animal care and maintenance, Ms. Yu-Chen, Huang for assistance with LC-MS/MS analyses, Ms. Shu-Chen, Shen for assistance with confocal microscopy. We also thank Ms. Miranda Loney of Academia Sinica for professional manuscript editing.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Heterogeneous nuclear ribonucleoprotein A1
KW - Immunogenic cell death
KW - Shikonin
KW - Tumor immunogenicity
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U2 - 10.18632/oncotarget.9660
DO - 10.18632/oncotarget.9660
M3 - Article
C2 - 27248319
AN - SCOPUS:84978772079
SN - 1949-2553
VL - 7
SP - 43629
EP - 43653
JO - Oncotarget
JF - Oncotarget
IS - 28
ER -