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

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.

• Authors: Shu-Yi Yin, Thomas Efferth, Feng-Yin Jian, Yung-Hsiang Chen, Chia-I Liu, Andrew H J Wang, Yet-Ran Chen, Pei-Wen Hsiao, Ning-Sun Yang
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 28 Pg. 43629-43653 (Jul 12 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27248319 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Cancer Vaccines
• Heterogeneous Nuclear Ribonucleoprotein A1
• Hnrnpa1 protein, mouse
• Naphthoquinones
• RNA, Messenger
• hnRNPA1 protein, human
• shikonin

Topics

• Animals
• Antineoplastic Agents (immunology, therapeutic use)
• Apoptosis (immunology)
• Breast Neoplasms (immunology, pathology, therapy)
• Cancer Vaccines (immunology)
• Cell Line, Tumor
• Dendritic Cells (immunology)
• Female
• Heterogeneous Nuclear Ribonucleoprotein A1 (immunology, metabolism)
• Humans
• Mice
• Mice, Inbred BALB C
• Molecular Docking Simulation
• Naphthoquinones (immunology, therapeutic use)
• RNA Processing, Post-Transcriptional (drug effects)
• RNA, Messenger (metabolism)
• Tandem Mass Spectrometry
• Xenograft Model Antitumor Assays