Abstract
BackgroundEmerging evidences suggests that Diosbulbin-B (DB) is effective to improve cisplatin (DDP)-sensitivity in gastric cancer (GC), but its molecular mechanisms were not fully delineated, and this study managed to investigate this issue.MethodsGenes expressions were determined by Real-Time qPCR and Western Blot at transcriptional and translational levels. Cell proliferation and viability were evaluated by cell counting kit-8 (CCK-8) and trypan blue staining assay. Annexin V-FITC/PI double staining assay was used to examine cell apoptosis. The Spheroid formation assay was used to evaluated cell stemness. The xenograft tumor-bearing mice models were established, and the tumors were monitored and the immunohistochemistry (IHC) was employed to examine the expressions and localization of Ki67 protein in mice tumor tissues.ResultsLow-dose DB (12.5 μM) downregulated PD-L1 to activate NLRP3-mediated pyroptosis, and inhibited cancer stem cells (CSCs) properties, to sensitize cisplatin-resistant GC (CR-GC) cells to cisplatin. Mechanistically, the CR-GC cells were obtained, and either low-dose DB or cisplatin alone had little effects on cell viability in CR-GC cells, while low-dose DB significantly induced apoptotic cell death in cisplatin treated CR-GC cells. In addition, low-dose DB triggered cell pyroptosis in CR-GC cells co-treated with cisplatin, which were abrogated by silencing NLRP3. Next, CSCs tended to be enriched in CR-GC cells, instead of their parental cisplatin-sensitive GC (CS-GC) cells, and low-dose DB inhibited spheroid formation and stemness biomarkers (SOX2, OCT4 and Nanog) expressions to eliminate CSCs in CR-GC cells, which were reversed by upregulating programmed death ligand-1 (PD-L1). Furthermore, we proved that PD-L1 negatively regulated NLRP3 in CR-GC cells, and low-dose DB activated NLRP3-mediated pyroptotic cell death in cisplatin treated CR-GC cells by downregulating PD-L1. Also, low-dose DB aggravated the inhibiting effects of cisplatin on tumorigenesis of CR-GC cells in vivo.ConclusionsCollectively, low-dose DB regulated intrinsic PD-L1/NLRP3 pathway to improve cisplatin-sensitivity in CR-GC cells, and this study provided alternative therapy treatments for GC.
Highlights
The therapeutic efficacy of the current chemical drugs for gastric cancer (GC) were seriously limited as the results of chemo-resistance [1,2,3], the development of new anti-tumor drugs for GC treatment became urgent and necessary
Low‐dose DB sensitized CR‐GC cells to cisplatin treatment DB had been used for cancer treatment [36, 37], and the previous data from our team indicated that low-dose DB (12.5 μM) was advantageous for GC treatment to avoid DB-induced hepatotoxicity [36], which rendered the possibility that low-dose DB (12.5 μM) might be a novel strategy to increase sensitivity of cisplatin-resistant GC (CR-GC) cells to the traditional chemotherapeutic drugs, such as cisplatin
The CR-GC cells (SGC7901/CDDP and BGC823/CDDP) were employed to establish xenograft tumor-bearing mice models, and we found that DB and cisplatin co-treatment significantly inhibited tumor weight (P < 0.05, Fig. 1f, Additional file 1: Figure S3) and volume (P < 0.05, Fig. 1g, h) to hamper tumorigenesis of the CR-GC cells in vivo
Summary
The therapeutic efficacy of the current chemical drugs for gastric cancer (GC) were seriously limited as the results of chemo-resistance [1,2,3], the development of new anti-tumor drugs for GC treatment became urgent and necessary. High-dose DB-induced hepatotoxicity [8], and the ineffectiveness of low-dose DB for cancer treatment seriously limited its utilization for GC treatment in clinic [5] To solve this issue, our preliminary work tried to use low-dose DB combined with genes manipulation to treat GC, and the results indicated that this strategy successfully hampered GC development, but had little detrimental effects on human normal hepatocytes (L-02) [5]. Emerging evidences suggests that Diosbulbin-B (DB) is effective to improve cisplatin (DDP)-sensitivity in gastric cancer (GC), but its molecular mechanisms were not fully delineated, and this study managed to investigate this issue
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