title: Modulation of P2X4/P2X7/Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death.
abstract: Overexpression of P2X7 receptors correlates with tumor growth and metastasis. Yet, release of ATP is associated with immunogenic cancer cell death as well as inflammatory responses caused by necrotic cell death at sites of trauma or ischemia-reperfusion injury. Using an FDA-approved anti-parasitic agent Ivermectin as a prototype agent to allosterically modulate P2X4 receptors, we can switch the balance between the dual pro-survival and cytotoxic functions of purinergic signaling in breast cancer cells. This is mediated through augmented opening of the P2X4/P2X7-gated Pannexin-1 channels that drives a mixed apoptotic and necrotic mode of cell death associated with activation of caspase-1 and is consistent with pyroptosis. We show that cancer cell death is dependent on ATP release and death signals downstream of P2X7 receptors that can be reversed by inhibition of NADPH oxidases-generated ROS, Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII) or mitochondrial permeability transition pore (MPTP). Ivermectin induces autophagy and release of ATP and HMGB1, key mediators of inflammation. Potentiated P2X4/P2X7 signaling can be further linked to the ATP rich tumor microenvironment providing a mechanistic explanation for the tumor selectivity of purinergic receptors modulation and its potential to be used as a platform for integrated cancer immunotherapy.
authors.affiliation: Department of Immuno-Oncology, City of Hope, Duarte, CA, US.
authors.forename: Dobrin
authors.initials: D
authors.lastname: Draganov
authors.affiliation: Department of Immuno-Oncology, City of Hope, Duarte, CA, US.
authors.forename: Sailesh
authors.initials: S
authors.lastname: Gopalakrishna-Pillai
authors.affiliation: Diabetes &Metabolism Research Institute, City of Hope, Duarte, CA, US.
authors.forename: Yun-Ru
authors.initials: YR
authors.lastname: Chen
authors.affiliation: Department of Immuno-Oncology, City of Hope, Duarte, CA, US.
authors.forename: Neta
authors.initials: N
authors.lastname: Zuckerman
authors.affiliation: Department of Immuno-Oncology, City of Hope, Duarte, CA, US.
authors.forename: Sara
authors.initials: S
authors.lastname: Moeller
authors.affiliation: Department of Immuno-Oncology, City of Hope, Duarte, CA, US.
authors.forename: Carrie
authors.initials: C
authors.lastname: Wang
authors.affiliation: Diabetes &Metabolism Research Institute, City of Hope, Duarte, CA, US.
authors.forename: David
authors.initials: D
authors.lastname: Ann
authors.affiliation: Department of Immuno-Oncology, City of Hope, Duarte, CA, US.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Lee
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000494:Allosteric Regulation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D017630:Connexins / Q000378:metabolism*; D006801:Humans; D007559:Ivermectin / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D058848:Receptors, Purinergic P2X4 / Q000235:genetics / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D017630:Connexins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009419:Nerve Tissue Proteins; C492764:PANX1 protein, human; D017382:Reactive Oxygen Species; D058848:Receptors, Purinergic P2X4; D058486:Receptors, Purinergic P2X7; D007559:Ivermectin; D000255:Adenosine Triphosphate; D019255:NADPH Oxidases; D011065:Poly(ADP-ribose) Polymerases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D020170:Caspase 1