Hyperthermia and associated changes in membrane fluidity potentiate P2X7 activation to promote tumor cell death
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Paola de Andrade Mello1,2,*, Shu Bian2,3,*, Luiz Eduardo Baggio Savio2,4, Haohai Zhang2,5, Jingping Zhang6, Wolfgang Junger6, Márcia Rosângela Wink7, Guido Lenz8, Andréia Buffon1, Yan Wu2,** and Simon Christopher Robson2,**
1Laboratório de Análises Bioquímicas e Citológicas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA
3Department of Gastroenterology, Tianjin Union Medical Center, Tianjin, P.R. China
4Programa de Imunobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
5Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
6Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA
7Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil
8Departamento de Biofísica e Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
**Joint senior authors
Simon Christopher Robson, email: [email protected]
Yan Wu, email: [email protected]
Keywords: purinergic signaling, hyperthermia, membrane fluidity, cancer therapy, colon cancer
Received: February 22, 2017 Accepted: May 22, 2017 Published: June 21, 2017
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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