Abstract
Gallbladder cancer (GBC) is a demanding fatal disease with no ideal treatment for inoperable patients. Recent reports have determined TNF-α associated lymphatic metastasis in GBC, while its resistance to TNF-α-killing remains largely unexplored. In this assay, we first found cellular inhibitor of apoptosis (cIAP1) overexpressed in GBC tissues and the roles in promoting the proliferation and migration of GBC in vitro as its homology cIAP2 does. Then how GBC cell survives TNF-α toxicity and TNF-α-induced apoptosis first prevail as follows. The reduction in cIAP1 does not give rise to apoptosis even with the stimulation of TNF-α. Importantly, the loss of cIAP1 enhanced TNF-α/cycloheximide-induced apoptosis in higher activation statuses of Caspase-8, Caspase-3 without the induction of Complex Ⅱ. In response to TNF-α, the reduction in cIAP1 caused the suppression in nuclear factor-κB (NF-κB) pathway and inhibition of transcription of cell death regulator cellular FLICE-like Inhibitory Protein (c-FLIP) instead. To conclude, cIAP1 is an oncological protein abundant in GBC tissues, which enhances proliferation and immigration and blocks TNF-α from apoptosis through NF-κB pathway in vitro.
Highlights
Gallbladder cancer (GBC) ranks the sixth highest incidence in digestion system cancer worldwide, characterized as one of the most demanding cancers [1]
TNF-α binds to TNFR in the membrane to form Complex by recruiting cellular inhibitor of apoptosis 1/2 to enhance the translocation of nuclear factor-κB (NF-κB) subunits into the nucleus and promote the transcription of various cytokines and proteins that mediate the progression of cancer or in another aspect, rescue cells from the fatal threats
The expression of cellular inhibitor of apoptosis protein (cIAP1) is up-regulated in GBC tissues
Summary
Gallbladder cancer (GBC) ranks the sixth highest incidence in digestion system cancer worldwide, characterized as one of the most demanding cancers [1]. Insights into certain oncological molecules, which is heated in both basic research and translational medicine, may fuel targeted therapies that overcome GBC in the future. It is well acknowledged that oncological behaviors of a tumor are attributed to the overexpressed molecules and its interaction with its embedded microenvironment. One of the most well-investigated cytokines flooded in the tumor microenvironment is TNF-α, which is capable of embarking on two distinct pathways in deciding life and death of cell [4,5]. TNF-α binds to TNFR in the membrane to form Complex by recruiting cellular inhibitor of apoptosis 1/2 (cIAP1/2) to enhance the translocation of NF-κB subunits into the nucleus and promote the transcription of various cytokines and proteins that mediate the progression of cancer or in another aspect, rescue cells from the fatal threats. TNF-α sets off apoptosis via inducing the formation of cytoplasmic Complex where Caspase-8 is cleaved into biologically functional ones, followed by activation of the Caspase cascade and proteolysis of the whole cell in the end
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