Photodynamic therapy causes cross-linking of signal transducer and activator of transcription proteins and attenuation of interleukin-6 cytokine responsiveness in epithelial cells

Photodynamic therapy (PDT) is a local treatment of cancers. The principle of PDT is the production of reactive oxygen species, in particular singlet oxygen, by light activation of a pholosensitizer introduced into the target cells. The direct photochemical and subsequent redox reactions can lead to cell death. This study sought to identify effects occurring during PDT and some of their consequences in surviving cells. Using epithelial cells in tissue culture and in tumors, several distinct PDT-mediated reactions were found, including global dephosphorylation of proteins, induced phosphorylation of a 71-kDa protein, initiation of cellular stress responses, structural modification and loss of epidermal growth factor receptor, and cross-linking of proteins. Specific covalent cross-linking of nonactivated signal transducer and activator of transcription (STAT)-3, and to a lesser extent of STAT1 and STAT4, correlated with PDT dose. Cross-linked STAT3 was primarily localized to the cytoplasm and failed to bind to DNA. The combination of STAT cross-linking and inactivation of receptor functions rendered PDT-treated cells refractory for at least 24 hours to interleukin-6 and oncostatin M, cytokines known to be elevated at site of tissue damage and inflammation. It is suggested that the loss of responsiveness to these inflammatory cytokines in the PDT-treated field assists tumor cells in evading the growth-suppressive activity of these mediators expected to be present at tissue sites after PDT.