SA-49, a novel aloperine derivative, induces MITF-dependent lysosomal degradation of PD-L1

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.

Autophagy Modulation in Human Thyroid Cancer Cells following Aloperine Treatment

“…Aloperine, a natural alkaloid isolated from the herb S. alopecuroides , has been reported to exhibit anticancer activity in various human cancers [1,7,12,15,18,20]. Previous studies have demonstrated that aloperine mediates cell proliferation, cell cycle inhibition and regulation, apoptosis induction, and tumor migration/invasion and suppression [1,7,12,15,18,19,26].…”

“…Aloperine, a quinolizidine alkaloid isolated from Sophora alopecuroides , reportedly exhibits multiple pharmacological activities, including anti-inflammatory, antiallergenic, antiviral, antimicrobial, antinociceptive, and antitumor effects; moreover, it exhibits protective effects against renal and neuronal injuries as well as pulmonary fibrosis [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]. Aloperine exerts antitumor effects against multiple human cancers, including multiple myeloma; colon, breast, prostate, and thyroid cancers; and osteosarcoma [1,7,12,15,18,20]. In previous studies, our and other research groups have demonstrated that aloperine can suppress tumorigenesis, inhibit tumor cell proliferation, and induce cell cycle arrest and apoptosis in various human cancer cells [1,7,12,15,18,19].…”

“…In previous studies, our and other research groups have demonstrated that aloperine can suppress tumorigenesis, inhibit tumor cell proliferation, and induce cell cycle arrest and apoptosis in various human cancer cells [1,7,12,15,18,19]. Studies investigating the mechanisms underlying the antitumor activity of aloperine have demonstrated the modulation of various signaling pathways in human tumors, including JAK/STAT3, Ras-Erk, and PI3K/Akt pathways, following aloperine treatment [1,7,13,15,19,20]. Furthermore, an in vivo study has demonstrated the safety and efficacy of aloperine as a therapeutic agent [7].…”

Research Progress on Anti‐Inflammatory Effects and Mechanisms of Alkaloids from Chinese Medical Herbs

“…After the application of aloperine, the injury of pulmonary vascular endothelial cells gets significantly improved, the shape of the nucleus of endothelial cells becomes basically normal, and the expansion of the Golgi body and endoplasmic reticulum gets improved. It suggests that rotenone can improve pulmonary hypertension induced by monocrotaline through the NF-κB p65 signaling pathway [50].…”

Identification of Aloperine as an anti-apoptotic Bcl2 protein inhibitor in glioma cells

“…Heretofore, ALO has been reported to exert therapeutic effects against pulmonary hypertension, renal injury and colon cancer (Zimecki, 1987). ALO derivatives with a unique endocyclic scaffold have also been designed, synthesized and evaluated as HCV, PD-L1 and HIV-1 entry inhibitors (Dang et al, 2016; Zhang et al, 2019). Moreover, analysis demonstrated that ALO suppresses tumorigenesis, suggesting its potential therapeutic use in human cancers and multidrug-resistant cancers.…”