Cx25 contributes to leukemia cell communication and chemosensitivity.
Cx25 contributes to leukemia cell communication and chemosensitivity.
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DOI：
10.18632/oncotarget.5226
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发表时间：
2015-10-13
期刊：
影响因子：
--
通讯作者：
Lathia JD
中科院分区：
文献类型：
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作者：
Sinyuk M;Alvarado AG;Nesmiyanov P;Shaw J;Mulkearns-Hubert EE;Eurich JT;Hale JS;Bogdanova A;Hitomi M;Maciejewski J;Huang AY;Saunthararajah Y;Lathia JD
白血病包括几种具有共同表型的血液恶性肿瘤，包括快速增殖、异常白细胞自我更新和随后的正常造血破坏。虽然白血病细胞和周围基质之间的通信支持肿瘤存活和扩展，但直接白血病细胞-细胞通信的机制及其对肿瘤生长的贡献尚不明确。间隙连接是由连接蛋白组成的专门的细胞间连接，其允许小分子和离子直接在相邻细胞的细胞质之间自由扩散。为了表征同型白血病细胞通信，我们采用了急性髓性白血病（AML）和急性淋巴细胞白血病（ALL）的体外模型，并通过染料转移试验测量了间隙连接功能。此外，临床相关的间隙连接抑制剂，甘珀酸（CBX）和1-辛醇，用于解偶联白血病细胞的通信能力。此外，qRT-PCR筛选揭示了与正常造血干细胞相比，白血病细胞中具有更高表达的几种连接蛋白。Cx 25被认为是一个有前途的辅助治疗靶点，通过RNA干扰减少Cx 25而不是Cx43减少了细胞间通讯，并使细胞对化疗敏感。综上所述，我们的数据表明，通过Cx 25依赖性间隙连接机制，白血病中存在同型通讯，可用于开发抗白血病疗法。
Leukemia encompasses several hematological malignancies with shared phenotypes that include rapid proliferation, abnormal leukocyte self-renewal, and subsequent disruption of normal hematopoiesis. While communication between leukemia cells and the surrounding stroma supports tumor survival and expansion, the mechanisms underlying direct leukemia cell-cell communication and its contribution to tumor growth are undefined. Gap junctions are specialized intercellular connections composed of connexin proteins that allow free diffusion of small molecules and ions directly between the cytoplasm of adjacent cells. To characterize homotypic leukemia cell communication, we employed in vitro models for both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and measured gap junction function through dye transfer assays. Additionally, clinically relevant gap junction inhibitors, carbenoxolone (CBX) and 1-octanol, were utilized to uncouple the communicative capability of leukemia cells. Furthermore, a qRT-PCR screen revealed several connexins with higher expression in leukemia cells compared with normal hematopoietic stem cells. Cx25 was identified as a promising adjuvant therapeutic target, and Cx25 but not Cx43 reduction via RNA interference reduced intercellular communication and sensitized cells to chemotherapy. Taken together, our data demonstrate the presence of homotypic communication in leukemia through a Cx25-dependent gap junction mechanism that can be exploited for the development of anti-leukemia therapies.