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Isolinderalactone Suppresses the Progression of Cholangiocarcinoma by Modulating the CARMA1-BCL10-MALT1 Signalosome

ABSTRACT: Cholangiocarcinoma (CCA) is a highly aggressive malignancy with poor prognosis and limited therapeutic options. While Isolinderalactone (ILL) has shown anticancer potential, its effects and underlying mechanisms in CCA remain unclear. This study investigated the anti-CCA activity of ILL and elucidated its molecular mechanisms. ILL significantly inhibited CCA cell viability, proliferation, migration, and invasion, while also inducing G0/G1 cell cycle arrest and promoting apoptosis. Transcriptomic and biochemical analyses revealed that ILL suppressed the NF-κB signaling pathway by inhibiting IκB phosphorylation and p65 activation. Mechanistically, ILL was found to directly bind to BCL10, a key adaptor protein. This interaction disrupted the formation of the CARMA1-BCL10-MALT1 (CBM) signalosome and consequently reduced BCL10 ubiquitination. Functional experiments confirmed this mechanism: BCL10 knockdown mimicked ILL's inhibitory effects, while a BCL10 mutation abolished them. Furthermore, activation of NF-κB with Diprovocim partially reversed ILL's suppressive effects. In a xenograft nude mouse model, ILL effectively reduced tumor growth without significant toxicity and suppressed NF-κB activation in tumor tissues. These findings demonstrate that Isolinderalactone suppresses CCA progression by modulating the CBM signalosome and BCL10 ubiquitination to regulate the NF-κB pathway, supporting its potential as a promising therapeutic candidate for CCA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE318264 | GEO | 2026/06/24

REPOSITORIES: GEO

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Project description:MALT lymphoma is characterized by t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/BCL10-IGH and t(14;18)(q32;q21)/IGH-MALT1, which commonly activate the NF-κB pathway. Gastric MALT lymphomas harboring such translocation do not respond to H. pylori eradication, while those without translocation can be cured by antibiotics. To understand the molecular mechanism of these different MALT lymphoma subgroups, we performed gene expression profiling analysis of 24 MALT lymphomas (15 translocation-positive, 9 translocation-negative). Gene set enrichment analysis (GSEA) of the NF-κB target genes and 4394 additional gene sets covering various cellular pathways, biological processes and molecular functions showed that translocation-positive MALT lymphomas are characterized by an enhanced expression of NF-κB target genes, particularly TLR6, CCR2, CD69 and BCL2, while translocation-negative cases were featured by active inflammatory and immune responses, such as IL8, CD86, CD28 and ICOS. Separate analyses of the genes differentially expressed between translocation-positive and negative cases and measurement of gene ontology term in these differentially expressed genes by hypergeometric test reinforced the above findings by GSEA. Finally, expression of TLR6, in the presence of TLR2, enhanced both API2-MALT1 and BCL10 mediated NF-κB activation in vitro. Our findings provide novel insights into the molecular mechanism of MALT lymphomas with and without translocation, potentially explaining their different clinical behaviors. This study compares MALT with other lymphomas namely follicular and mantle cell lymphomas, and investigates the molecular mechanisms of the lymphomagenesis between translocation positive versus negative MALT lymphoma cases in order to derive the pathways leading to MALT lymphoma pathogenesis using GSEA, GO, dynamic pathway analysis as well as other bioinformatics analysis. Samples were run on the Affymetrix HG-U133A and HG-U133 plus2 GeneChips.

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Isolinderalactone Suppresses the Progression of Cholangiocarcinoma by Modulating the CARMA1-BCL10-MALT1 Signalosome

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