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.
Highlights
Immunogenic cell death (ICD) is a cell death modality that effectively stimulates an immune response against dying or dead cell antigens, in particular when they are derived from cancerous cells [1,2,3]
We and others previously reported that shikonin (SK), a phytochemical derived from the medicinal plant Lithospermum erythrorhizon (LE), can serve as an efficacious adjuvant for expression of damage-associated molecular patterns (DAMPs) and the subsequent induction of ICD in treated carcinoma cells [3, 8]
SK and its analogs have been indicated to be potent inhibitors of a tumorspecific pyruvate kinase-M2 (PKM2) [25], a potential molecular target for disrupting glucose metabolism in cancer cells [26, 27]. We identified another molecular target of SK, namely heterogeneous nuclear ribonucleoprotein A1, which is known to play a key role in lymphocyte-induced ICD in targeted cells [3, 13, 14, 23]
Summary
Immunogenic cell death (ICD) is a cell death modality that effectively stimulates an immune response against dying or dead cell antigens, in particular when they are derived from cancerous cells [1,2,3]. We and others previously reported that shikonin (SK), a phytochemical derived from the medicinal plant Lithospermum erythrorhizon (LE), can serve as an efficacious adjuvant for expression of damage-associated molecular patterns (DAMPs) and the subsequent induction of ICD in treated carcinoma cells [3, 8]. This SK-treated tumor cell lysate (SKTCL) can be further employed to induce strong in vivo anti-tumor activity for a dendritic cell (DC)-based cancer vaccine [8, 11]. The identification of hierarchical regulatory mechanisms of SK will be necessary and important for www.impactjournals.com/oncotarget future clinical application of the SK-induced cellular ICD in development of cancer immunotherapy
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