29th Annual Meeting of the American Society of Photobiology

Downtown Marriot

Chicago, Il.

Role of the mitogen activated protein kinase (MAPK) signaling pathways in the sensitivity of human cells to photodynamic therapy

Abstract-
During photodynamic therapy (PDT) a photosensitive drug is retained by tumor cells and activated by visible light to produce reactive oxygen species which can lead to several cellular responses including cell cycle arrest, necrosis, apoptosis and the activation of many signal transduction pathways. Although the mitogen-activated protein kinases (MAPKs) are thought to play a critical role in the cellular response to radiotherapy and chemotherapy , their role following PDT is less clear. We have previously reported that normal human fibroblasts show increased sensitivity to Photofrin-mediated PDT compared to immortalized Li-Fraumeni syndrome (LFS) cells. In order to examine the role of MAPKs in the cellular sensitivity to PDT, we have investigated the response of the c-Jun N-terminal kinase-1 (JNK1), the p38 MAPK and the extracellular signal regulated protein kinases 1 and 2 (ERK1/2) in a normal human fibroblast strain (GM38A) and in an LFS cell line following Photofrin-mediated PDT at equivalent cellular Photofrin levels. The activation of JNK-1, p38 and ERK1/2 was observed at 30 min following PDT in both cell types. For GM38A cells the activation of MAPKs was transient and decreased to near MAPK levels in untreated cells or less by 2 to 3 h after PDT. In contrast, for the LFS cells, MAPK levels substantially above that in untreated cells were maintained for at least 11 h after PDT. The difference in cellular response was most pronounced for activation of ERK1/2 where in GM38A cells PDT actually resulted in an inhibition of ERK1/2 phosphorylation by 3 h after PDT, whereas a substantially enhanced ERK1/2 level was maintained in LFS cells for at least 11 h. Pre-treatment of LFS cells with PD58095 (75M), a MEK1/2-specific inhibitor, reduced PDT-induced ERK1/2 phosphorylation by more than 50% and significantly reduced cell viability suggesting that prolonged activation of ERK1/2 contributes to the resistance of LFS cells to PDT. These results suggest that one or more of the MAPK signaling pathways plays a role in the sensitivity of some human cells to Photofrin-mediated PDT. (This work was supported by a National Institute of Health, USA, Program Grant and the National Cancer Institute of Canada with funds from the Canadian Cancer Society)

Keywords: Photofrin-mediated photodynamic therapy, mitogen activated kinases, cellular sensitivity to photodynamic therapy