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Neoplastic pancreatic epithelial cells are widely believed to die via Caspase 8-dependantapoptotic cell death and chemotherapy is thought to further promote tumor apoptosis. Conversely, disruption of apoptosis is a basic modality cancer cells exploit for survival. However, the role of necroptosis, or programmed necrosis, in pancreatic ductal adenocarcinoma (PDA) is uncertain. There are a multitude of potential inducers of necroptosis in PDA including ligation of TNFR1, CD95, TRAIL receptors, Toll-like receptors, ROS, and Chemotherapeutics. We doscovered that the principal components of the necrosome, RIP1 and RIP3, are highly expressed in PDA and are further upregulated by chemotherapy. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. However, belying these findings, in vivo RIP3 deletion or RIP1 inhibition was protective against …