Interleukin-6 trans signalling enhances photodynamic therapy by modulating cell cycling
Journal
British Journal of Cancer
Journal Volume
97
Journal Issue
11
Pages
1513-1522
Date Issued
2007
Author(s)
Abstract
Photodynamic therapy (PDT) of solid tumours causes tissue damage that elicits local and systemic inflammation with major involvement of interleukin-6 (IL-6). We have previously reported that PDT-treated cells lose responsiveness to IL-6 cytokines. Therefore, it is unclear whether PDT surviving tumour cells are subject to regulation by IL-6 and whether this regulation could contribute to tumour control by PDT. We demonstrate in epithelial tumour cells that while the action of IL-6 cytokines through their membrane receptors is attenuated, regulation by IL-6 via trans-signalling is established. Soluble interleukin-6 receptor-α (IL-6Rα) (sIL-6Rα) and IL-6 were released by leucocytes in the presence of conditioned medium from PDT-treated tumour cells. Cells that had lost their membrane receptor IL-6Rα due to PDT responded to treatment with the IL-6R-IL-6 complex (Hyper-IL-6) with activation of signal transducers and activator of transcription (STAT3) and ERK. Photodynamic therapy-treated cells, which were maintained during post-PDT recovery in presence of IL-6 or Hyper-IL-6, showed an enhanced suppression of proliferation. Cytokine-dependent inhibition of proliferation correlated with a decrease in cyclin E, CDK2 and Cdc25A, and enhancement of p27kip1 and hypophosphorylated Rb. The IL-6 trans-signalling-mediated attenuation of cell proliferation was also effective in vivo detectable by an improved Colon26 tumour cure by PDT combined with Hyper-IL-6 treatment. Prevention of IL-6 trans-signalling using soluble gp130 reduced curability. The data suggest that the post-PDT tumour milieu contains the necessary components to establish effective IL-6 trans-signalling, thus providing a means for more effective tumour control. ? 2007 Cancer Research.
Subjects
Cell cycle; Interleukin-6; Photodynamic therapy; Soluble interleukin-6 receptor
SDGs
Other Subjects
2 (1 hexyloxyethyl) 2 devinylpyropheophorbide a; cyclin dependent kinase 2; cyclin dependent kinase inhibitor 1B; cyclin E; glycoprotein gp 130; interleukin 6; interleukin 6 receptor; mitogen activated protein kinase 3; photosensitizing agent; protein tyrosine phosphatase; retinoblastoma protein; STAT3 protein; unclassified drug; animal cell; animal experiment; animal model; article; cancer control; cell cycle; cell proliferation; controlled study; cytokine release; human; human cell; mouse; nonhuman; photodynamic therapy; priority journal; protein expression; protein phosphorylation; signal transduction; solid tumor; tumor cell; Animals; Blotting, Western; cdc25 Phosphatases; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Chlorophyll; Colonic Neoplasms; Culture Media, Conditioned; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p27; Dose-Response Relationship, Drug; Hela Cells; Humans; Interleukin-6; Macrophages; Mice; Mice, Inbred BALB C; Photochemotherapy; Receptors, Interleukin-6; Signal Transduction; STAT3 Transcription Factor
Type
journal article