Na-K-Cl cotransporter in Glioblastoma Multiforme

多形性胶质母细胞瘤中的 Na-K-Cl 协同转运蛋白

• 批准号: 8856372
• 负责人: Dandan Sun
• 金额: $ 38.54万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8856372
• 关键词: Apoptosis; Apoptotic; Bumetanide; Caspase; Categories; Cell Death; Cell Survival; Cell Volumes; Cells; Cessation of life; Characteristics; DNA; DNA Damage; DNA Repair; Data; Enzymes; Family; Glioblastoma; Glioma; Homeostasis; In Vitro; Infiltration; Ion Transport; Ionic Strengths; Ions; Isotonic Exercise; Lesion; Light; Lysine; Malignant - descriptor; Malignant Neoplasms; Mediating; Methyltransferase; Patients; Phosphotransferases; Play; Primary Brain Neoplasms; Process; Protein Isoforms; Protein-Serine-Threonine Kinases; Proteins; Regulation; Resected; Resistance; Role; Signal Pathway; Small Interfering RNA; Stimulus; Survival Rate; Testing; Time; Water; World Health Organization; Xenograft Model; base; cancer cell; cancer stem cell; chemoradiation; chemotherapy; chloride-cotransporter potassium; genetic regulatory protein; improved; inhibitor/antagonist; novel; novel therapeutics; response; solute; symporter; temozolomide; tumor growth; tumor xenograft

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is a World Health Organization Grade IV cancer, the most malignant category of glial tumors with median survival time less than one year. The combined temozolomide (TMZ)-mediated chemoradiotherapy only modestly improves survival of GBM patients [2-yr survival rate of 27%] and 80% of totally resected GBM recur. The key challenge in the treatment is an increase of a subpopulation of GBM cancer cells which are resistant to apoptosis. Therefore, new strategies are needed to improve the efficiency of the current therapies for GBM. TMZ causes a DNA O6-methylguanine lesion which triggers DNA repair, depletes the enzyme O6-methylguanine methyltransferase, and leads to apoptotic cell death. The hallmark of apoptosis is a drastic reduction in cell volume resulting from loss of K+i and Cl-i, termed apoptotic volume decrease "AVD". AVD is an ubiquitous characteristic of apoptosis which is independent of the death stimuli. Loss of cell volume and reduction of total intracellular ionic strength (via loss of K+ and Cl-) occur before any other detectable characteristics of apoptosis. The reduction of intracellular ionic strength has been suggested to play a permissive role in activation of caspases and triggering the entire caspase cascade and apoptotic machinery. Normally, cells respond to volume perturbations by activating volume regulatory mechanisms. The process by which shrunken cells return to normal volume is termed regulatory volume increase (RVI). RVI can only be regulated by the gain of osmotically active solutes such as Na+, K+ and Cl-. Na+-K+-2Cl- co-transporter isoform 1 (NKCC1), which transports 1 Na+, 1 K+ and 2 Cl- ions into the cell, is the primary cell volume regulatory protein in RVI in response to either hypertonic or isotonic cell shrinkage. Therefore, NKCC1-mediated RVI will promote cell survival. However, it remains unexplored whether NKCC1-mediated K+, Cl- accumulation can counteract AVD, restore intracellular ionic strength, reduce caspase-mediated apoptosis, and promote cell survival in response to TMZ-mediated DNA damage. Our preliminary data illustrate that NKCC1 is the most important ion transport mechanism in regulating Cl-i and RVI in GBM cancer cells. Interestingly, pharmacological blockade of NKCC1 activity with its potent inhibitor bumetanide enhanced TMZ- mediated apoptosis. This led us to hypothesize that NKCC1 activity is stimulated in the TMZ-treated cells and its inhibition can sensitize glioma to TMZ-mediated apoptosis. Completion of this study will shed light on whether a combined TMZ-based therapy with NKCC1 inhibition presents a novel therapeutic strategy, which may increase the efficiency of the current chemotherapy.

描述(申请人提供)：多形性胶质母细胞瘤(GBM)是世界卫生组织IV级癌症，是中位生存期不到一年的恶性程度最高的神经胶质肿瘤。替莫唑胺(TMZ)介导的联合放化疗仅适度提高了GBM患者的存活率[2年存活率为27%]和80%的完全切除的GBM复发。治疗中的关键挑战是抗凋亡的GBM癌细胞亚群的增加。因此，需要新的策略来提高目前治疗基底膜的效率。TMZ导致DNA O6-甲基鸟嘌呤损伤，从而触发DNA修复，耗尽O6-甲基鸟嘌呤甲基转移酶，并导致细胞凋亡。细胞凋亡的特征是K+i和Cl-i的丢失导致细胞体积急剧缩小，称为凋亡体积减小。AVD是细胞凋亡的普遍特征，不受死亡刺激的影响。细胞体积的丧失和细胞内总离子强度的降低(通过K+和Cl-的丧失)发生在任何其他可检测到的细胞凋亡特征之前。细胞内离子强度的降低被认为在激活caspase和触发整个caspase级联和凋亡机制中起着允许的作用。正常情况下，细胞通过激活体积调节机制来响应体积扰动。收缩的细胞恢复正常体积的过程被称为调节性体积增加(RVI)。RVI仅受渗透活性物质如Na+、K+和Cl-的增益调节。Na+-K+-2Cl-共转运蛋白1(NKCC1)是RVI中主要的细胞体积调节蛋白，可将1个Na+、1个K+和2个Cl-离子转运到细胞内，对高渗或等渗细胞收缩作出反应。因此，NKCC1介导的RVI将促进细胞存活。然而，NKCC1介导的K+，Cl-蓄积是否可以对抗AVD，恢复细胞内离子强度，减少caspase介导的细胞凋亡，促进细胞存活，以应对TMZ介导的DNA损伤，目前尚不清楚。我们的初步数据表明，NKCC1是调节GBM癌细胞中Cl-I和RVI的最重要的离子转运机制。有趣的是，用其有效的抑制剂布美他尼阻断NKCC1的活性可以促进TMZ介导的细胞凋亡。这导致我们假设TMZ处理的细胞中NKCC1的活性被刺激，它的抑制可以使胶质瘤对TMZ介导的细胞凋亡敏感。这项研究的完成将阐明基于TMZ和抑制NKCC1的联合治疗是否提供了一种新的治疗策略，可能会提高当前化疗的效率。

项目成果

Synthetic analogues of the montanine-type alkaloids with activity against apoptosis-resistant cancer cells.

• DOI: 10.1016/j.bmcl.2018.01.041
• 发表时间: 2018-02-15
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Govindaraju K;Ingels A;Hasan MN;Sun D;Mathieu V;Masi M;Evidente A;Kornienko A
• 通讯作者: Kornienko A

Blockade of Na/H exchanger stimulates glioma tumor immunogenicity and enhances combinatorial TMZ and anti-PD-1 therapy.

• DOI: 10.1038/s41419-018-1062-3
• 发表时间: 2018-09-27
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Guan X;Hasan MN;Begum G;Kohanbash G;Carney KE;Pigott VM;Persson AI;Castro MG;Jia W;Sun D
• 通讯作者: Sun D

Elevated Na/H exchanger 1 (SLC9A1) emerges as a marker for tumorigenesis and prognosis in gliomas.

• DOI: 10.1186/s13046-018-0923-z
• 发表时间: 2018-10-17
• 期刊: Journal of experimental & clinical cancer research : CR
• 作者: Guan X;Luo L;Begum G;Kohanbash G;Song Q;Rao A;Amankulor N;Sun B;Sun D;Jia W
• 通讯作者: Jia W