Mechanism by which the molecular glue-like verteporfin induces IRE1α dimerization and activation to synergize with AKT inhibition in breast cancer

IF 7.2 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology Pub Date : 2025-06-19 DOI:10.1016/j.chembiol.2025.05.004

Yongliang Liu , Hui Hua , Yalan Cao , Minjing Li , Hongying Zhang , Shan Du , Jieya Liu , Ting Luo , Yangfu Jiang

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Abstract

Inositol-requiring enzyme 1α (IRE1α) signaling is one of three arms of the unfolded protein response, playing a vital role in maintaining endoplasmic reticulum homeostasis. Pharmacological modulation of this pathway offers potential therapeutic strategies for various diseases. Molecular glues may regulate protein stability and activity by inducing protein-protein interaction. Here, we find that verteporfin functions as a molecular glue, promoting IRE1α dimerization and activation. Specifically, verteporfin binds to IRE1α, facilitating its dimerization, which relies on the His692 residue. This activation of IRE1α triggers XBP1 splicing and miR-153-mediated downregulation of PTEN, along with AKT phosphorylation. Additionally, we identify the pro-metastasis gene BACH1 as a novel target of miR-153, which is downregulated by IRE1α and verteporfin. While verteporfin inhibits breast cancer cell viability and invasion, its combination with an AKT inhibitor synergistically suppresses breast cancer progression. Our findings establish a mechanistic link between IRE1α and PI3K/AKT signaling, highlighting a possibility for therapeutic intervention.

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分子胶样维替波芬诱导乳腺癌中IRE1α二聚化和活化协同抑制AKT的机制

肌醇要求酶1α (IRE1α)信号是未折叠蛋白反应的三个分支之一，在维持内质网稳态中起着至关重要的作用。该通路的药理调节为多种疾病提供了潜在的治疗策略。分子胶可以通过诱导蛋白质相互作用来调节蛋白质的稳定性和活性。在这里，我们发现维替泊芬作为一种分子胶，促进IRE1α二聚化和活化。具体来说，verteporfin与IRE1α结合，促进其二聚化，这依赖于His692残基。IRE1α的激活触发XBP1剪接和mir -153介导的PTEN下调，以及AKT磷酸化。此外，我们确定了转移前基因BACH1作为miR-153的新靶点，miR-153被IRE1α和维替波特芬下调。虽然维替波芬抑制乳腺癌细胞活力和侵袭，但它与AKT抑制剂联合使用可协同抑制乳腺癌的进展。我们的研究结果建立了IRE1α和PI3K/AKT信号之间的机制联系，强调了治疗干预的可能性。

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来源期刊

Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

14.70

自引率

2.30%

发文量

143

期刊介绍： Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.