de Andrade Mello Paola, Bian Shu, Savio Luiz Eduardo Baggio, Zhang Haohai, Zhang Jingping, Junger Wolfgang, Wink Márcia Rosângela, Lenz Guido, Buffon Andréia, Wu Yan, Robson Simon Christopher
Laboratório de Análises Bioquímicas e Citológicas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA.
Oncotarget. 2017 Jun 21;8(40):67254-67268. doi: 10.18632/oncotarget.18595. eCollection 2017 Sep 15.
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.
肿瘤微环境（TME）中细胞外ATP（eATP）的积累有可能激活嘌呤能信号传导。eATP引发的信号效应可增强抗肿瘤免疫反应，同时对肿瘤细胞和血管内皮细胞发挥直接细胞毒性作用，至少部分是通过P2X7受体介导的。增强TME中嘌呤能信号传导的方法，例如通过外切核苷酸酶CD39阻断和/或增强P2X7功能反应，可能用作癌症治疗中的免疫调节疗法。在本研究中，我们阐述了热疗的可转化策略，以证明其对P2X7对eATP反应性的影响。注意到热疗（40°C）可增强eATP对MCA38结肠癌细胞的细胞毒性。热疗诱导的膜流动性增加增强了P2X7功能，增强了孔开放并调节下游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共同显著增强癌细胞死亡。我们的数据表明，具有调节的P2X7-嘌呤能信号传导的临床可耐受热疗将提高传统癌症治疗的疗效。
