Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation.
Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation.
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DOI：
10.1371/journal.pbio.1001320
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发表时间：
2012
期刊：
影响因子：
9.8
通讯作者：
Quiñones-Hinojosa A
中科院分区：
文献类型：
--
作者：
Garzon-Muvdi T;Schiapparelli P;ap Rhys C;Guerrero-Cazares H;Smith C;Kim DH;Kone L;Farber H;Lee DY;An SS;Levchenko A;Quiñones-Hinojosa A
离子转运蛋白NKCC1通过调节细胞粘附和生长因子信号传导之间的相互作用来决定脑肿瘤细胞的迁移，是治疗脑癌的潜在治疗靶点。胶质母细胞瘤（GB）是一种高度侵袭性和致命性的脑肿瘤，因为其普遍复发。尽管有人认为电中性的 Na+-K+-Cl− 协同转运蛋白 1 (NKCC1) 在神经胶质瘤细胞迁移中发挥作用，但这种离子转运蛋白导致 GB 侵袭性的确切机制仍知之甚少。在这里，我们重点研究了 NKCC1 在体外和体内人原代胶质瘤细胞侵袭中的作用。 GB 和间变性星形细胞瘤组织中的 NKCC1 表达水平显着高于 II 级胶质瘤和正常皮质。药理学抑制和 shRNA 介导的 NKCC1 表达敲低导致体内外细胞迁移和侵袭减少。令人惊讶的是，在神经胶质瘤细胞中敲低 NKCC1 导致形成明显更大的粘着斑和细胞牵引力，比对照细胞低约 40%。表皮生长因子 (EGF) 可促进神经胶质瘤细胞迁移，通过 PI3K 依赖性机制增加 NKCC1 的磷酸化。这一发现可能与 WNK 激酶有关。综上所述，我们的研究结果表明 NKCC1 通过两种不同的机制调节神经胶质瘤细胞的迁移：（1）通过调节粘着斑动力学和细胞收缩性；（2）通过离子转运调节细胞体积。由于 NKCC1 在哺乳动物组织中普遍表达，WNK 激酶对其的调节可能作为 GB 侵袭性的新治疗靶点，并可用于其他高度侵袭性肿瘤。许多癌症的治疗受到肿瘤细胞侵袭能力的阻碍。一个显着的例子是脑癌，由于其侵袭性以及手术切除后肿瘤复发率高，因此无法治愈。在这里，我们进一步分析了 NKCC1 的功能，NKCC1 是一种离子转运蛋白，已知可调节细胞体积和细胞内氯离子浓度，并在脑肿瘤细胞侵袭中发挥重要作用。我们的研究结果表明，除了作为离子转运蛋白的常规功能外，NKCC1 还可能与细胞骨架相互作用，并通过充当锚定点，在细胞迁移过程中将收缩力从质膜传递到细胞外基质，从而影响脑肿瘤细胞的迁移。此外，我们发现，非常规酶家族WNK激酶对NKCC1的调节是影响NKCC1活性的重要因素，并可能决定脑肿瘤细胞的侵袭能力。我们假设 NKCC1 在脑肿瘤细胞迁移中具有多种功能，鉴于这些蛋白质在全身的广泛表达，NKCC1 与其调节酶一起可能成为治疗脑肿瘤或其他类型癌症的治疗靶点。
The ion transporter NKCC1 determines brain tumor cell migration by regulating the interplay between cell adhesion and growth factor signaling, and is a potential therapeutic target to treat brain cancer. Glioblastoma (GB) is a highly invasive and lethal brain tumor due to its universal recurrence. Although it has been suggested that the electroneutral Na+-K+-Cl− cotransporter 1 (NKCC1) can play a role in glioma cell migration, the precise mechanism by which this ion transporter contributes to GB aggressiveness remains poorly understood. Here, we focused on the role of NKCC1 in the invasion of human primary glioma cells in vitro and in vivo. NKCC1 expression levels were significantly higher in GB and anaplastic astrocytoma tissues than in grade II glioma and normal cortex. Pharmacological inhibition and shRNA-mediated knockdown of NKCC1 expression led to decreased cell migration and invasion in vitro and in vivo. Surprisingly, knockdown of NKCC1 in glioma cells resulted in the formation of significantly larger focal adhesions and cell traction forces that were approximately 40% lower than control cells. Epidermal growth factor (EGF), which promotes migration of glioma cells, increased the phosphorylation of NKCC1 through a PI3K-dependant mechanism. This finding is potentially related to WNK kinases. Taken together, our findings suggest that NKCC1 modulates migration of glioma cells by two distinct mechanisms: (1) through the regulation of focal adhesion dynamics and cell contractility and (2) through regulation of cell volume through ion transport. Due to the ubiquitous expression of NKCC1 in mammalian tissues, its regulation by WNK kinases may serve as new therapeutic targets for GB aggressiveness and can be exploited by other highly invasive neoplasms. Treatment of many cancers has been hampered by the invasive ability of tumor cells. A notable example is brain cancer, which is incurable due to its invasiveness and resulting high tumor recurrence after surgical resection. Here, we analyze further the function of NKCC1, an ion transporter that is known to regulate cell volume and intracellular chloride concentration, and to play an important role in brain tumor cell invasion. Our findings suggest that in addition to its conventional function as an ion transporter, NKCC1 may also interact with the cytoskeleton and affect brain tumor cell migration by acting as an anchor that transduces contractile forces from the plasma membrane to the extracellular matrix en route to cell migration. Moreover, we show that regulation of NKCC1 by a family of unconventional enzymes, the WNK kinases, is an important factor that affects the activity of NKCC1 and may determine the invasive ability of brain tumor cells. We postulate that NKCC1 has multiple functions in brain tumor cell migration and that together with its regulatory enzymes may be therapeutic targets in the treatment of brain tumors or other types of cancer, given the wide expression of these proteins throughout the body.
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影响因子：
3
作者：
Chaichana KL;Guerrero-Cazares H;Capilla-Gonzalez V;Zamora-Berridi G;Achanta P;Gonzalez-Perez O;Jallo GI;Garcia-Verdugo JM;Quiñones-Hinojosa A
通讯作者：
Quiñones-Hinojosa A
影响因子：
2.5
作者：
BIRK, DE;NURMINSKAYA, MV;ZYCBAND, EI
通讯作者：
ZYCBAND, EI
DOI：
10.1073/pnas.86.12.4549
发表时间：
1989-06-01
影响因子：
11.1
作者：
BIRK, DE;ZYCBAND, EI;TRELSTAD, RL
通讯作者：
TRELSTAD, RL
影响因子：
6.3
作者：
Grimm, I.;Ullsperger, S. N.;Zimmermann, H.
通讯作者：
Zimmermann, H.
影响因子：
7.8
作者：
Beningo, KA;Dembo, M;Wang, YL
通讯作者：
Wang, YL