Venetoclax synergizes with Wnt/β-catenin inhibitor C-82 in acute myeloid leukemia by increasing the degradation of Mcl-1 protein.

IF 5.3 2区医学 Q1 ONCOLOGY

Cancer Cell International Pub Date : 2025-05-29 DOI:10.1186/s12935-025-03825-8

Mengya Pan, Changqing Jiao, Menghua Sun, Duo Jin, Yin Wang, Haoxuan Wu, Yan Zhang, Enbo Chen, Bobin Su, Junjie Zhou, Xiaoying Liu, Jian Ge

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引用次数: 0

Abstract

Background: Due to compensatory survival signalling and overexpression of anti-apoptotic Bcl-2 family proteins, the majority of AML patients developed acquired resistance of venetoclax (VEN) to combination therapy of VEN with low-dose cytarabine (LDAC) or hypomethylating agents (HMAs). Dysregulation of the Wnt/β-catenin signalling pathway is intently associated with leukemia development and chemotherapy resistance. However, there is currently no Wnt/β-catenin inhibitor approved for clinical use and it is not clear whether targeting the Wnt/β-catenin pathway enhances the anti-leukemic activity of VEN.

Methods: Analysis of the AML patient's data in the BeatAML and GEO databases. Establishing the MOLM13 venetoclax-resistant cell line (MOLM13-R cells) based on the MOLM13 parental cell line. CCK-8, Annexin-V/PI and Western blotting were performed to assess the effects of the combination of Wnt/β-catenin inhibitor C-82 and VEN in AML cell lines. The potential mechanisms of synergistic effects of the two-drug combination were explored by Western blotting and ubiquitination immunoprecipitation.

Results: We displayed that the expression of β-catenin abnormally upregulated in AML patients and MOLM13-R cells. Knockdown of β-catenin could increase cell apoptosis in MOLM13-R cells. Combined treatment of C-82 with VEN synergistically inhibited AML cell growth and increased apoptosis. Mechanistically, C-82 disrupted the stability of Mcl-1 protein, and Mcl-1 downregulation was associated with different phosphorylation sites of Mcl-1 and proteasomal degradation. The combination of C-82 and VEN synergistically induced concurrent mitochondrial-associated apoptosis and gasdermin E (GSDME)-dependent pyroptosis.

Conclusion: Our findings propose an effective treatment strategy for AML patients through the combination of C-82 and VEN, positioning this regimen as a promising therapeutic option.

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Venetoclax通过增加Mcl-1蛋白的降解，与Wnt/β-catenin抑制剂C-82协同治疗急性髓系白血病。

背景：由于代偿性生存信号和抗凋亡Bcl-2家族蛋白的过度表达，大多数AML患者对ventoclax （VEN）与低剂量阿糖胞苷（LDAC）或低甲基化药物（HMAs）联合治疗产生获得性耐药。Wnt/β-catenin信号通路的失调与白血病的发展和化疗耐药性密切相关。然而，目前还没有Wnt/β-catenin抑制剂被批准用于临床，也不清楚靶向Wnt/β-catenin通路是否能增强VEN的抗白血病活性。方法：分析BeatAML和GEO数据库中AML患者的数据。以MOLM13亲本细胞系为基础，建立MOLM13抗venetoclaxis细胞系（MOLM13- r细胞）。通过CCK-8、Annexin-V/PI和Western blotting检测Wnt/β-catenin inhibitor C-82与VEN联合应用对AML细胞株的影响。采用免疫印迹法和泛素化免疫沉淀法探讨两药联合增效的潜在机制。结果：我们发现β-catenin在AML患者和MOLM13-R细胞中表达异常上调。敲低β-catenin可增加MOLM13-R细胞的凋亡。C-82与VEN联合治疗可协同抑制AML细胞生长并增加凋亡。在机制上，C-82破坏了Mcl-1蛋白的稳定性，Mcl-1的下调与Mcl-1的不同磷酸化位点和蛋白酶体降解有关。C-82和VEN联合可协同诱导线粒体相关细胞凋亡和GSDME依赖性热亡。结论：我们的研究结果提出了一种通过C-82和VEN联合治疗AML患者的有效治疗策略，将该方案定位为一种有前景的治疗选择。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell International ONCOLOGY-

CiteScore

10.90

自引率

1.70%

发文量

360

审稿时长

1 months

期刊介绍： Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.