Targeting Glutathione S-transferase M4 in Ewing sarcoma.
Targeting Glutathione S-transferase M4 in Ewing sarcoma.
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DOI：
10.3389/fped.2014.00083
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发表时间：
2014
影响因子：
2.6
通讯作者：
Luo W
中科院分区：
文献类型：
--
作者：
Zhuo R;Kosak KM;Sankar S;Wiles ET;Sun Y;Zhang J;Ayello J;Prestwich GD;Shami PJ;Cairo MS;Lessnick SL;Luo W
尤文氏肉瘤是一种儿童骨和软组织的恶性肿瘤。虽然局部疾病的5年生存率接近75%，但尽管广泛使用积极的治疗策略，转移性和/或耐药性疾病的预后仍然令人沮丧。我们以前报道过谷胱甘肽S-转移酶M4（GSTM 4）在原发性肿瘤中的高表达与患者预后不良相关。GSTM 4是尤文肉瘤细胞致癌转化所必需的，并介导对化疗药物的耐药性。在这里，我们对尤文肉瘤细胞进行了RNA测序分析，并将我们的结果与公开的数据集相结合，以证明GSTM 4是尤文肉瘤中特异性表达的主要GST。使用泛GST抑制剂6-（7-硝基-2，1，3-苯并恶二唑-4-基硫基）己醇（NBDHEX）药理学抑制GSTM 4活性显著限制尤文肉瘤细胞的细胞增殖和致癌转化。此外，NBDHEX和依托泊苷的组合使用协同增加细胞毒性，表明GSTM 4作为细胞凋亡抑制剂的作用。机制研究表明，GSTM 4由于其与凋亡信号调节激酶1（ASK 1）相互作用并通过c-Jun N-末端激酶轴抑制信号传导的能力而限制凋亡。为了利用我们观察到的GSTM 4表达在尤文肉瘤中特异性上调，我们测试了GSTM 4激活的抗癌剂O2-（2，4-二硝基苯基）1-[（4-乙氧羰基）哌嗪-1-基]二氮烯-1-鎓-1，2-二醇盐或JS-K对肿瘤生长和存活的影响。我们发现JS-K可显著降低尤文肉瘤细胞活力和异种移植肿瘤生长，并改善异种移植小鼠的总体存活率。我们的数据表明，GSTM 4是一个新的治疗靶点，用于治疗高GSTM 4表达的尤文肉瘤。将联合收割机与抑制GSTM 4、由GSTM 4激活或阻断GSTM 4/ASK 1相互作用的药物组合的策略可能比标准治疗方法更特异和/或有效。
Ewing sarcoma is a malignant pediatric bone and soft tissue tumor. Although the 5-year survival rate of localized disease approaches 75%, the prognosis of metastatic and/or therapy-resistant disease remains dismal despite the wide use of aggressive therapeutic strategies. We previously reported that high expression of glutathione S-transferase M4 (GSTM4) in primary tumors correlates with poor patient outcomes. GSTM4 is required for oncogenic transformation and mediates resistance to chemotherapeutic drugs in Ewing sarcoma cells. Here, we performed RNA-sequencing analyses of Ewing sarcoma cells and combined our results with publicly available datasets to demonstrate that GSTM4 is a major GST specifically expressed in Ewing sarcoma. Pharmacological inhibition of GSTM4 activity using a pan GST inhibitor, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX), significantly limited cellular proliferation and oncogenic transformation of Ewing sarcoma cells. Moreover, combined use of NBDHEX and etoposide synergistically increased cytotoxicity, suggesting a role for GSTM4 as an inhibitor of apoptosis. Mechanistic studies revealed that GSTM4 limits apoptosis owing to its ability to interact with Apoptosis Signal-regulating Kinase 1 (ASK1) and inhibit signaling via the c-Jun N-terminal Kinase axis. To exploit our observation that GSTM4 expression is specifically up-regulated in Ewing sarcoma, we tested the effect of a GSTM4-activated anti-cancer agent, O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate or JS-K, on tumor growth and survival. We found that JS-K robustly decreased Ewing sarcoma cell viability and xenograft tumor growth and improved overall survival of xenograft mice. Our data suggest that GSTM4 is a novel therapeutic target for the treatment of high GSTM4-expressing Ewing sarcoma. Strategies that combine standard chemotherapy with agents that inhibit GSTM4, that are activated by GSTM4, or that block GSTM4/ASK1 interactions, can potentially be more specific and/or efficacious than standard therapeutic approaches.
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影响因子：
4.7
作者：
Luo W;Kinsey M;Schiffman JD;Lessnick SL
通讯作者：
Lessnick SL
影响因子：
11.2
作者：
Baird, K;Davis, S;Meltzer, PS
通讯作者：
Meltzer, PS
影响因子：
11.2
作者：
Federici, Luca;Lo Sterzo, Carlo;Caccuri, Anna Maria
通讯作者：
Caccuri, Anna Maria
影响因子：
4.8
作者：
Cho, SG;Lee, YH;Choi, EJ
通讯作者：
Choi, EJ
影响因子：
4.8
作者：
Ricci, G;De Maria, F;Caccuri, AM
通讯作者：
Caccuri, AM