Extracellular Leakage Protein Patterns in Two Types of Cancer Cell Death: Necrosis and Apoptosis

[Image: see text] Dead cells release fragments of DNA, RNA, and proteins (including peptides) into the extracellular space. Two major forms of cell death during cancer development have been identified: necrosis and apoptosis. Our group investigated the mechanisms that regulate cell death during the treatment of mouse tumor FM3A cells with the anticancer drug floxuridine (FUdR). In the original strain F28-7, FUdR induced necrosis, whereas in the variant F28-7-A, it induced apoptosis. Here, we report that the extracellular leakage proteome (i.e., the secretome) is involved in these cell death phenomena. The secretome profile, which was analyzed via shotgun proteomic analysis, revealed that altered protein leakage was involved in signal transduction, transcription, RNA processing, translation, and cell death. Notably, the characteristic secretory proteins high mobility group box 1 and 2 were detected in the culture medium of both necrotic and apoptotic cells. Overall, these results indicate that unique cellular events mediated by secretory proteins may be involved in necrosis and apoptosis.