ArticleEBioMedicine2019
SA-49, a novel aloperine derivative, induces MITF-dependent lysosomal degradation of PD-L1.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 73 citations in OpenAlex.
- MS1-96 induces HIP1R-dependent PD-L1 degradation and promotes antitumor immunity in colorectal cancer.Acta pharmacologica Sinica · 2026Article
- Disruption of FGL2 induces TFEB-dependent lysosomal degradation of PD-L1 and enhances the efficacy of anti-PD1 therapy in hepatocellular carcinoma.Cell communication and signaling : CCS · 2026Article
- Intracellular PD-L1: Functions, Regulation, and Therapeutic Implications.International journal of biological sciences · 2026Review
- Small molecules targeting the PD-1/PD-L1 axis for cancer immunotherapy.Theranostics · 2026Review
- Article
- TFE3 fusion proteins promoted the progression of Xp11.2 translocation renal cell carcinoma through post-translational modification of PDL1 by upregulating CCND1/Cyclin D1.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Suppression of tumor growth by GMI, an edible fungal immunomodulatory protein, is associated with targeting GSK3β‑mediated proteasomal degradation of PD‑L1.International journal of molecular medicine · 2025Article
- D-mannose suppresses the angiogenesis and progression of colorectal cancer.Acta biochimica et biophysica Sinica · 2025Article
- PKCα regulates the secretion of PDL1-carrying small extracellular vesicles in a p53-dependent manner.Cell death & disease · 2025Article
- Polygonatum polysaccharides as gut microbiota modulators: implications for autophagy-dependent PD-L1 clearance in cancer immunotherapy.Frontiers in nutrition · 2025Review
- Differentiation status determines the effects of IFNγ on the expression of PD-L1 and immunomodulatory genes in melanoma.Cell communication and signaling : CCS · 2024Article
- Beyond inhibition against the PD-1/PD-L1 pathway: development of PD-L1 inhibitors targeting internalization and degradation of PD-L1.RSC medicinal chemistry · 2024Review
- From immune checkpoints to therapies: understanding immune checkpoint regulation and the influence of natural products and traditional medicine on immune checkpoint and immunotherapy in lung cancer.Frontiers in immunology · 2024Review
- Challenges Coexist with Opportunities: Spatial Heterogeneity Expression of PD-L1 in Cancer Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Review
- Inhibition of CK2/ING4 Pathway Facilitates Non-Small Cell Lung Cancer Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Aloperine targets lysosomes to inhibit late autophagy and induces cell death through apoptosis and paraptosis in glioblastoma.Molecular biomedicine · 2023Article
- D-mannose induces TFE3-dependent lysosomal degradation of EGFR and inhibits the progression of NSCLC.Oncogene · 2023Article
- USP2 promotes tumor immune evasion via deubiquitination and stabilization of PD-L1.Cell death and differentiation · 2023Article
- Dynamical modeling of proliferative-invasive plasticity and IFNγ signaling in melanoma reveals mechanisms of PD-L1 expression heterogeneity.Journal for immunotherapy of cancer · 2023Article
- Regulation of PD-L1 Trafficking from Synthesis to Degradation.Cancer immunology research · 2023Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundProgrammed death-ligand 1 (PD-L1) is a T-cell inhibitory checkpoint molecule that suppresses antitumor immunity. Anti-PD-L1 antibodies have shown remarkable promise in treating tumors, but the patient response rate is low. Therefore, small-molecule checkpoint inhibitors blocking PD-L1 function are urgently needed.
methodsChanges of protein expression and phosphorylation levels were determined by immunoblotting. The level of Membrane PD-L1 was examined by flow cytometer. Cytotoxicity of T cells and NK cells toward tumor cells were detected using LDH and cell index assays. Lysosome function was investigated by NAG assay. Changes in lysosomal-related genes were measured by RT-PCR. In vivo anti-NSCLC cancer effects were assessed using C57BL/6 mice bearing Lewis tumor xenografts.
findingsWe identified SA-49 as a new regulator of PD-L1 expression from a series of novel aloperine derivatives. SA-49 decreased the expression of PD-L1 in NSCLC cells and enhanced the cytotoxicity of co-cultured T and NK cells toward tumor cells. Importantly, lysosomal pathway contributed to SA-49-mediated down-regulation of PD-L1. SA-49 increased the biogenesis of lysosome and promoted translocation of PD-L1 to lysosome for proteolysis, which was associated with nuclear translocation of MITF. SA-49-induced MITF translocation acted through activation of PKCα and subsequently suppression of GSK3β activity. Furthermore, SA-49 suppressed Lewis tumor xenograft growth by activating immune microenvironment in C57BL/6 mice.
interpretationOur data demonstrate that SA-49 can be used to regulate PD-L1 in cancer cells and trigger its degradation by activating lysosome function.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.