Critical role of gap junction communication, calcium and nitric oxide signaling in bystander responses to focal photodynamic injury

Bianca Calì, Stefano Ceolin, Federico Ceriani, Mario Bortolozzi, Andrielly H R Agnellini, Veronica Zorzi, Andrea Predonzani, Vincenzo Bronte, Barbara Molon, Fabio Mammano

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
Pages (from-to)10161-10174
Number of pages14
JournalOncotarget
Volume6
Issue number12
Publication statusPublished - 2015

Keywords

  • Calcium signaling
  • Cancer
  • Connexins
  • Nitric oxide
  • Photodynamic therapy

ASJC Scopus subject areas

  • Oncology

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