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.
| Original language | English |
|---|---|
| Pages (from-to) | 43629-43653 |
| Number of pages | 25 |
| Journal | Oncotarget |
| Volume | 7 |
| Issue number | 28 |
| DOIs | |
| Publication status | Published - 2016 |
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Keywords
- Heterogeneous nuclear ribonucleoprotein A1
- Immunogenic cell death
- Shikonin
- Tumor immunogenicity
ASJC Scopus subject areas
- Oncology
Cite this
Immunogenicity of mammary tumor cells can be induced by shikonin via direct binding-interference with hnRNPA1. / 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.
In: Oncotarget, Vol. 7, No. 28, 2016, p. 43629-43653.Research output: Contribution to journal › Article
}
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
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
UR - http://www.scopus.com/inward/record.url?scp=84978772079&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84978772079&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.9660
DO - 10.18632/oncotarget.9660
M3 - Article
C2 - 27248319
AN - SCOPUS:84978772079
VL - 7
SP - 43629
EP - 43653
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 28
ER -