Different Faces of Fas Signaling in Cancer Cells

Abstract

The Fas signaling is known to exert very variable effects in wide spectrum of cells. The FasR/ FasL (CD95/ CD95L) proteins can be associated with both positive (physiological) and negative (pathological) effects. Nowadays, there is a growing interest in the elucidation of the Fas signaling role in the pathogenesis and progression of various cancers. Additionally, it was proven that the expression of FasR/ FasL in colorectal cancer is associated with worse prognosis, metastasis and recurrence [1-6] the aspects of cancer biology which cancer stem cells are responsible for [7]. On the one hand, Fas signaling pathway is considered as a potential target for anticancer therapy and, on the other hand, is hoped to be exploit as therapeutic tool. The approach to this issue is dynamically update since the state of knowledge concerning Fas signaling functions is rapidly developing. The most established pro-apoptotic activity of FasR/L signaling is the elimination of non-CSC cancerous, virus-infected or useless/ autoreactive T cells by cytotoxic T lymphocytes [8]. Drug therapy combining the multi-kinase inhibitor Sorafenib and the histone deacetylase inhibitor Vorinostat was shown to activate Fas-mediated apoptosis by promoting receptor tyrosine phosphorylation or contribution to FasR activation via initial facilitation of ROS generation and subsequent FasL expression [9]. Additionally, Fas signaling was proven to be associated with HSPs. Although it was originally demonstrated in rat global brain ischemia model, we assume that similar relationships exist in cancer cells as well. Inhibition of HSP90 proteins reduced FasL expression and induced neuroprotective effect [10]. Moreover, the heat shock proteins accumulation was demonstrated as a specific mechanism increasing protein stability and reducing a turnover during Fas-mediated apoptosis in Jurkat cells [11].