Journal
ONCOTARGET
Volume 6, Issue 12, Pages 10161-10174Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3553
Keywords
cancer; photodynamic therapy; nitric oxide; calcium signaling; connexins
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Funding
- University of Padua [CPDA094904]
- Italian Ministry of Health, Italian Ministry of Education, Universities, and Research [FIRB cup: B31J11000420001]
- Italian Association for Cancer Research (AIRC) [6599, 12182, 14103]
- Italian Ministry of Health [BANDO GIOVANI RICERCATORI 2009 - GR-2009-1558698]
- Cariparo Fundation Fellowship
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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 Ca2+-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.
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