Produção Nacional
Hyperthermia and associated changes in membrane fluidity potentiate P2X7 activation to promote tumor cell death
2017; Impact Journals LLC; Volume: 8; Issue: 40 Linguagem: Inglês
10.18632/oncotarget.18595
ISSN1949-2553
AutoresPaola de Andrade Mello, Bian Shu, Luiz Eduardo Baggio Savio, Haohai Zhang, Jingping Zhang, Wolfgang G. Junger, Michaël Wink, Guido Lenz, Andréia Buffon, Yan Wu, Simon C. Robson,
Tópico(s)Autophagy in Disease and Therapy
Resumo// Paola de Andrade Mello 1, 2, * , Shu Bian 2, 3, * , Luiz Eduardo Baggio Savio 2, 4 , Haohai Zhang 2, 5 , Jingping Zhang 6 , Wolfgang Junger 6 , Márcia Rosângela Wink 7 , Guido Lenz 8 , Andréia Buffon 1 , Yan Wu 2, ** and Simon Christopher Robson 2, ** 1 Laboratório de Análises Bioquímicas e Citológicas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil 2 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA 3 Department of Gastroenterology, Tianjin Union Medical Center, Tianjin, P.R. China 4 Programa de Imunobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil 5 Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China 6 Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA 7 Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil 8 Departamento de Biofísica e Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil * Co-first author ** Joint senior authors Correspondence to: Simon Christopher Robson, email: srobson@bidmc.harvard.edu Yan Wu, email: ywu@bidmc.harvard.edu Keywords: purinergic signaling, hyperthermia, membrane fluidity, cancer therapy, colon cancer Received: February 22, 2017 Accepted: May 22, 2017 Published: June 21, 2017 ABSTRACT 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.
Referência(s)