title: Critical role of gap junction communication, calcium and nitric oxide signaling in bystander responses to focal photodynamic injury.
abstract: Ionizing and nonionizing radiation affect not only directly targeted cells but also surrounding "bystander" cells. The underlying mechanisms and therapeutic role of bystander responses remain incompletely defined. Here we show that photosentizer activation in a single cell triggers apoptosis in bystander cancer cells, which are electrically coupled by gap junction channels and support the propagation of a Ca2+ wave initiated in the irradiated cell. The latter also acts as source of nitric oxide (NO) that diffuses to bystander cells, in which NO levels are further increased by a mechanism compatible with Ca(2+)-dependent enzymatic production. We detected similar signals in tumors grown in dorsal skinfold chambers applied to live mice. Pharmacological blockade of connexin channels significantly reduced the extent of apoptosis in bystander cells, consistent with a critical role played by intercellular communication, Ca2+ and NO in the bystander effects triggered by photodynamic therapy.
authors: Foundation for Advanced Biomedical Research, Venetian Institute of Molecular Medicine, Padua, Italy.|University of Padua, Department of Surgery Oncology and Gastroenterology, Oncology and Immunology Section, Padua, Italy.
authors: Bianca
authors: B
authors: Calì
authors: University of Padua, Department of Physics and Astronomy, Padua, Italy.
authors: Stefano
authors: S
authors: Ceolin
authors: Foundation for Advanced Biomedical Research, Venetian Institute of Molecular Medicine, Padua, Italy.|University of Padua, Department of Physics and Astronomy, Padua, Italy.
authors: Federico
authors: F
authors: Ceriani
authors: Foundation for Advanced Biomedical Research, Venetian Institute of Molecular Medicine, Padua, Italy.|University of Padua, Department of Physics and Astronomy, Padua, Italy.
authors: Mario
authors: M
authors: Bortolozzi
authors: Foundation for Advanced Biomedical Research, Venetian Institute of Molecular Medicine, Padua, Italy.|University of Padua, Department of Surgery Oncology and Gastroenterology, Oncology and Immunology Section, Padua, Italy.
authors: Andrielly H R
authors: AH
authors: Agnellini
authors: Foundation for Advanced Biomedical Research, Venetian Institute of Molecular Medicine, Padua, Italy.|University of Padua, Department of Physics and Astronomy, Padua, Italy.
authors: Veronica
authors: V
authors: Zorzi
authors: IRCCS, Istituto Oncologico Veneto, Padua, Italy.
authors: Andrea
authors: A
authors: Predonzani
authors: Foundation for Advanced Biomedical Research, Venetian Institute of Molecular Medicine, Padua, Italy.|Verona University Hospital, Department of Pathology and Diagnostics, Immunology Section, Verona, Italy.
authors: Vincenzo
authors: V
authors: Bronte
authors: IRCCS, Istituto Oncologico Veneto, Padua, Italy.
authors: Barbara
authors: B
authors: Molon
authors: Foundation for Advanced Biomedical Research, Venetian Institute of Molecular Medicine, Padua, Italy.|University of Padua, Department of Physics and Astronomy, Padua, Italy.|Present address: CNR, Institute of Cell Biology and Neurobiology, Monterotondo (RM), Italy.
authors: Fabio
authors: F
authors: Mammano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002450:Cell Communication; D017630:Connexins / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D010778:Photochemotherapy / Q000379:methods*; D015398:Signal Transduction
chemical_list: D017630:Connexins; D009569:Nitric Oxide; D002118:Calcium
keywords: calcium signaling; cancer; connexins; nitric oxide; photodynamic therapy