Hyperthermia and associated changes in membrane fluidity potentiate P2X7 activation to promote tumor cell death.
Hyperthermia and associated changes in membrane fluidity potentiate P2X7 activation to promote tumor cell death.
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DOI：
10.18632/oncotarget.18595
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发表时间：
2017-09-15
期刊：
影响因子：
--
通讯作者：
Robson SC
中科院分区：
文献类型：
--
作者：
de Andrade Mello P;Bian S;Savio LEB;Zhang H;Zhang J;Junger W;Wink MR;Lenz G;Buffon A;Wu Y;Robson SC
肿瘤微环境(TME)中细胞外三磷酸腺苷(EATP)的积聚具有激活嘌呤能信号的潜能。EATP诱导的信号效应增强了抗肿瘤免疫反应，同时对肿瘤细胞和血管内皮细胞产生直接细胞毒作用，至少部分通过P2X7受体介导。在TME中增强嘌呤能信号的方法，例如通过阻断CD39，和/或增强P2X7功能反应，可能被用作癌症治疗的免疫调节疗法。在这项研究中，我们描绘了热疗的可翻译策略，以展示对P2X7对eATP的响应的影响。热疗(40℃)可增强eATP介导的对MCA38结肠癌细胞的杀伤作用。高温诱导的膜流动性增加增强了P2X7的功能，增强了孔的开放，并调节了下游的AKT/PRAS40/mTOR信号事件。当与顺铂或丝裂霉素C联合使用时，热疗和eATP一起显著增强癌细胞的死亡。我们的数据表明，临床可耐受的热疗与调节的P2X7-嘌呤能信号将提高传统癌症治疗的疗效。
Extracellular ATP (eATP) accumulation within the tumor microenvironment (TME) has the potential to activate purinergic signaling. The eATP evoked signaling effects bolster antitumor immune responses while exerting direct cytotoxicity on tumor cells and vascular endothelial cells, mediated at least in part through P2X7 receptors. Approaches to augment purinergic signaling in TME e.g. by ectonucleotidase CD39 blockade, and/or boosting P2X7 functional responses, might be used as immunomodulatory therapies in cancer treatment. In this study, we delineated the translatable strategy of hyperthermia to demonstrate impacts on P2X7 responsiveness to eATP. Hyperthermia (40°C) was noted to enhance eATP-mediated cytotoxicity on MCA38 colon cancer cells. Increased membrane fluidity induced by hyperthermia boosted P2X7 functionality, potentiating pore opening and modulating downstream AKT/PRAS40/mTOR signaling events. When combined with cisplatin or mitomycin C, hyperthermia and eATP together markedly potentiate cancer cell death. Our data indicate that clinically tolerable hyperthermia with modulated P2X7-purinergic signaling will boost efficacy of conventional cancer treatments.
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影响因子：
3.1
作者：
Cihoric, Nikola;Tsikkinis, Alexandros;Ghadjar, Pirus
通讯作者：
Ghadjar, Pirus
影响因子：
5.5
作者：
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通讯作者：
Gorodeski, George I.
DOI：
10.1016/j.biocel.2015.09.001
发表时间：
2015-11-01
影响因子：
4
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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