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PP2A 调节通过 mPTP 依赖性细胞凋亡克服慢性淋巴细胞白血病的多药耐药性。

PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis.

机构信息

Department of Microbiology, Immunology, and Cancer Biology, University of Virginia (UVA) School of Medicine, Charlottesville, Virginia, USA.

Beirne B. Carter Center for Immunology Research, Charlottesville, Virginia, USA.

出版信息

J Clin Invest. 2023 Jul 3;133(13):e155938. doi: 10.1172/JCI155938.

DOI:10.1172/JCI155938
PMID:37166997
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10313372/
Abstract

Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins. Co-immunoprecipitation analyses with selective BH domain antagonists revealed that the pleiotropic proapoptotic protein (Bim) was prevented from activating Bax/Bak by "switching" interactions to other upregulated antiapoptotic proteins (Mcl-1, Bcl-xL, Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that small-molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug-resistant leukemia and lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug-resistant CLL cells through induction of mitochondrial permeability transition pores, independent of Bax/Bak. DT-061 inhibited the growth of wild-type and Bax/Bak double-knockout, multidrug-resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug-resistant CLL cells in patients and validated a pharmacologically tractable pathway to deplete this reservoir.

摘要

靶向治疗药物，如 venetoclax（VEN）（Bcl-2 抑制剂），彻底改变了慢性淋巴细胞白血病（CLL）的治疗方法。我们之前报道过，接受治疗的患者中的持续存在的 CLL 细胞过度表达多种抗凋亡蛋白，并对促凋亡剂产生耐药性。在这里，我们证明了体内多药耐药的 CLL 细胞由于 Bax 和 Bak（Bax/Bak）蛋白的激活不足，在早期线粒体水平表现出凋亡受限。与选择性 BH 结构域拮抗剂的共免疫沉淀分析表明，多效性促凋亡蛋白（Bim）通过与其他上调的抗凋亡蛋白（Mcl-1、Bcl-xL、Bcl-2）的“切换”相互作用，防止激活 Bax/Bak。因此，需要绕过 Bax/Bak 限制的治疗方法来耗尽患者体内这些耐药细胞。蛋白磷酸酶 2A（PP2A）有助于肿瘤发生和治疗耐药性。我们观察到，PP2A 的小分子激活剂（SMAP）在多种癌细胞系和 CLL 样本中诱导细胞毒性，包括多药耐药的白血病和淋巴瘤细胞。SMAP（DT-061）通过诱导线粒体通透性转换孔，独立于 Bax/Bak，在多药耐药的 CLL 细胞中诱导细胞凋亡。DT-061 在异种移植小鼠模型中抑制野生型和 Bax/Bak 双敲除、多药耐药的 CLL 细胞的生长。总之，我们在患者中发现了多药耐药的 CLL 细胞，并验证了一种具有药理学可操作性的途径来耗尽这种耐药细胞库。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6aff/10313372/afa2d7ca5bf7/jci-133-155938-g163.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6aff/10313372/c1910698f53a/jci-133-155938-g158.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6aff/10313372/5bbeeb751336/jci-133-155938-g159.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6aff/10313372/1f5cda89d5b9/jci-133-155938-g160.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6aff/10313372/75015597dc58/jci-133-155938-g161.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6aff/10313372/9531d94cd8c3/jci-133-155938-g162.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6aff/10313372/afa2d7ca5bf7/jci-133-155938-g163.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6aff/10313372/c1910698f53a/jci-133-155938-g158.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6aff/10313372/5bbeeb751336/jci-133-155938-g159.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6aff/10313372/1f5cda89d5b9/jci-133-155938-g160.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6aff/10313372/75015597dc58/jci-133-155938-g161.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6aff/10313372/afa2d7ca5bf7/jci-133-155938-g163.jpg

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