The Raf-kinase inhibitor protein (RKIP) plays a role in the regulation of different processes, through its interaction with several signaling pathways. These pathways include the mitogen activated protein kinase (MAPK), nuclear factor kappa-light chain enhancer of activated B cells (NF-κB), G protein-coupled receptors (GPCR) and glycogen synthase kinase 3 beta (GSK 3β). RKIP negatively affects tumor survival and proliferation, acting as a metastasis suppressor. Moreover, RKIP overexpression has been reported to reverse tumor chemo/immuno/radio-resistance and support the anticancer host immuno-surveillance. The aim of this work is to evaluate the role of RKIP in cancer cells during a photooxidative damage induced by photodynamic therapy (PDT). PDT treatment is based on three components: a photosensitizer, light and oxygen. Their combined action produces singlet oxygen (1O2) and/or reactive oxygen species (ROS) leading to an oxidative insult in tumor cells. Dependently on the PDT dose, the response of tumor cells can have a double outcome: stimulation of tumor cell proliferation with a low PDT dose (IC50), or tumor growth arrest in the case of a high PDT dose (IC50). We evaluated RKIP expression within its complex network, correlating with other factors involved in the tumor response to oxidative stress. We found a link between the expression of RKIP and NF-κB, MAPK, Snail and Nrf2 according to the type of the oxidative insult. In the presence of low PDT, RKIP is downregulated, while NF-κB, Snail and Nrf2 are upregulated: an expression profile that stimulates tumor proliferation and resistance. Conversely, RKIP is overexpressed in the case of high PDT, thus allowing an arrest of tumor growth.Considering that many antitumor drugs develop ROS/RNS causing disease recurrence and drug resistance, RKIP could be a good prognostic marker to follow patients' response to anticancer therapies.
