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.
Highlights
Adenosine triphosphate (ATP) is well known to provide the intracellular energy currency of cells, but is present at low levels in the extracellular space under physiological conditions
We have shown that cisplatin or mitomycin C in combination with hyperthermia and extracellular ATP is more effective in inducing cancer cell death
We have investigated whether hyperthermia would sensitize cancer cells to ATP cytotoxicity
Summary
Adenosine triphosphate (ATP) is well known to provide the intracellular energy currency of cells, but is present at low levels in the extracellular space under physiological conditions. Higher levels of extracellular ATP are perceived as a danger signal by cells in pathological processes [1]. The presence of high levels of extracellular ATP has been noted in the tumor microenvironment [2, 3]. Such heightened pericellular ATP levels have been demonstrated to increase tumor cell death through multiple mechanisms inclusive of: augmentation of antitumor immunity, direct induction of tumor cell death, and blockade of tumor angiogenesis [4, 5]. Antitumor actions of extracellular ATP may occur through activation of several type 2-purinergic receptors (P2R), P2X7 is far the most important ATPreceptor [1, 5]. P2X7 is the only P2X receptor capable to form a membrane pore permeable to large molecules (up to 900 Da), resulting in tumor cell apoptosis [6]
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