Chronic Inhibition of STAT3/STAT5 in Treatment-Resistant Human Breast Cancer Cell Subtypes: Convergence on the ROS/SUMO Pathway and Its Effects on xCT Expression and System xc- Activity.
Chronic Inhibition of STAT3/STAT5 in Treatment-Resistant Human Breast Cancer Cell Subtypes: Convergence on the ROS/SUMO Pathway and Its Effects on xCT Expression and System xc- Activity.
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DOI：
10.1371/journal.pone.0161202
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Singh G
中科院分区：
文献类型：
--
作者：
Linher-Melville K;Nashed MG;Ungard RG;Haftchenary S;Rosa DA;Gunning PT;Singh G
药物靶向激活的STAT3和/或STAT5一直是癌症研究的活跃领域。胱氨酸/谷氨酸逆向转运体系统XC-有助于氧化还原平衡和细胞内产生的谷氨酸的输出，以响应癌细胞中上调的谷氨酰胺分解。我们之前已经证明，用小分子抑制剂SH-4-54阻断STAT3/5，可以增加XCT的表达，从而增加人乳腺癌细胞中XC-系统的活性。SH-4-54针对这两种蛋白的SH2结构域。目前的研究表明，长期给予SH-4-54，然后克隆选择耐药的MDA-MB-231和T47D乳腺癌细胞，可以引起明显的亚型依赖效应。在三重阴性的MDA-MB-231细胞中，XCT的mRNA和蛋白水平、谷氨酸释放和半胱氨酸摄取比未经处理的传代匹配的对照细胞减少，而雌激素反应的T47D细胞则相反。这种“阴阳”效应与STAT3和STAT5的磷酸化状态、细胞内ROS水平以及STAT5的SUMO化/去SUMO化之间的平衡转移有关。STAT5在转录水平上是XCT的一个明确的负调控因子，而STAT3的激活伴随着系统XC-活性的增加。我们认为，仔细分类患者的乳腺癌亚型是有效地将STAT3/5作为治疗乳腺癌的一种治疗手段的核心，特别是考虑到XCT正在成为侵袭性癌症的重要生物标志物。
Pharmacologically targeting activated STAT3 and/or STAT5 has been an active area of cancer research. The cystine/glutamate antiporter, system xc-, contributes to redox balance and export of intracellularly produced glutamate in response to up-regulated glutaminolysis in cancer cells. We have previously shown that blocking STAT3/5 using the small molecule inhibitor, SH-4-54, which targets the SH2 domains of both proteins, increases xCT expression, thereby increasing system xc- activity in human breast cancer cells. The current investigation demonstrates that chronic SH-4-54 administration, followed by clonal selection of treatment-resistant MDA-MB-231 and T47D breast cancer cells, elicits distinct subtype-dependent effects. xCT mRNA and protein levels, glutamate release, and cystine uptake are decreased relative to untreated passage-matched controls in triple-negative MDA-MB-231 cells, with the inverse occurring in estrogen-responsive T47D cells. This “ying-yang” effect is linked with a shifted balance between the phosphorylation status of STAT3 and STAT5, intracellular ROS levels, and STAT5 SUMOylation/de-SUMOylation. STAT5 emerged as a definitive negative regulator of xCT at the transcriptional level, while STAT3 activation is coupled with increased system xc- activity. We propose that careful classification of a patient’s breast cancer subtype is central to effectively targeting STAT3/5 as a therapeutic means of treating breast cancer, particularly given that xCT is emerging as an important biomarker of aggressive cancers.