Two CD95 tumor classes with different sensitivities to antitumor drugs

Abstract

CD95 is a member of the family of the death receptors that initiate apoptosis by recruiting Fas-associated death domain protein (FADD), procaspase-8, procaspase-10, and cellular FLICE-like inhibitory protein to the death-inducing signaling complex (DISC), which forms after binding of the cognate ligand (CD95L) (1). CD95 type I and II cells differ in their dependence on mitochondria for the execution of apoptosis in that type II cells require mitochondrial amplification to die (2). Hence, overexpression of antiapoptotic Bcl-2 family members only inhibits CD95-mediated apoptosis in type II cells. We proposed this CD95 two-pathway model based on a study of four tumor cell lines (2, 3), and a number of transgenic and knockout mice have demonstrated that this distinction also applies to normal tissues (e.g., liver cells are type II, and T cells are type I) (reviewed in ref. 4). One of the most striking differences between type I and II cells lies in the way the CD95 signal is generated at the receptor level. An efficient formation of the DISC is observed only in type I cells, whereas in type II cells it is difficult to detect by Western blotting (2). We recently demonstrated that formation of the DISC in type I cells involves F-actin (5) and that the receptor internalizes in an actin-and caspase-8-dependent fashion only in type I cells (6). These data suggest that type I cells differ from type II cells in the way the CD95 signal is initiated. This difference in signal initiation could result in a difference in sensitivity to CD95 stimuli.The cognate CD95L is expressed as both a membrane-bound (mCD95L) and soluble (sCD95L) form that is generated by metalloprotease cleavage of mCD95L (7,8). As yet, no clear specific separate function has been assigned to sCD95L or mCD95L. Here we uncover a striking difference in the response of type I and II tumor cell lines to different forms of CD95L. We found that a preparation of soluble sCD95L (S2) (9) efficiently kills type II cells. In contrast, type I cells are resistant to this cytotoxic activity. S2 therefore represents a tool for identifying type I and II cells. We applied this tool to a collection of 58 tumor cell lines of various histologic origin [of the Developmental Therapeutics Program of the National Cancer Institute (NCI)] (10). These cell lines have been subjected to a comprehensive microarray analysis to determine their patterns of gene expression and were found to cluster into two very distinct classes of cells (epithelium-like and mesenchymal-like) that share expression of similar sets of genes (11). We have determined that 22 of these 58 cell lines are CD95 apoptosis-sensitive and have classified half of these sensitive cells as type I and half as type II based on their sensitivity to S2 stimulation and their ability to form a DISC. Ten of 11 of the cell lines that we classified as type I cells were found in the mesenchymal branch, whereas 9 of 11 of the type II cells were found in the epithelial branch. The type I͞type II status of the cells was used to query t...

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New insights into apoptosis signaling by Apo2L/TRAIL

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