Abstract
Recent studies showed that tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) induces the proliferation of squamous cell carcinoma (SCC) cells. However, the precise mechanism underlying such effect of TWEAK remains unclear. This study was designed to elucidate the role of cellular inhibitor of apoptosis 1 (cIAP1) in TWEAK-induced proliferation of SCC cells. Human SCC cells (SCC-13, A431, and SCC-9) were cultured in vitro, receiving the stimulation of TWEAK or TNF-related apoptosis-inducing ligand (TRAIL). We found that TWEAK induced cytoplasmic cIAP1 importation and RIP1 ubiquitination in cells, followed by the activation of canonical nuclear factor kappa B signals. MV1, a cIAP1 inhibitor, abrogated TWEAK-induced proliferation of these cells. Moreover, the interaction between TWEAK and its receptor, fibroblast growth factor-inducible 14 (Fn14), enhanced the expression of TRAIL receptor types 3 and 4 (TRAIL-R3/4). Furthermore, the transfection of TRAIL-R3/4 siRNA abrogated the promotion effect of TWEAK on SCC-13 cell proliferation and cIAP1 expression. Therefore, TWEAK/Fn14 interaction promotes the proliferation of SCC cells through activating cIAP1 signals. Targeting the downstream cIAP1 signals might attenuate the effect of TWEAK on SCC cells.
Highlights
Tumor necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK) is a soluble cytokine and belongs to the members of the tumor necrosis factor (TNF) superfamily
Our results demonstrated that the mRNA expression levels of TNF-related apoptosis-inducing ligand (TRAIL) receptor type 1 (TRAIL-R1) and TRAIL-R2 were not affected in squamous cell carcinoma (SCC)-13 cells by TNF-like weak inducer of apoptosis (TWEAK) stimulation (0 to 1000 ng/ml) while both TRAIL-R3 and TRAIL-R4 increased with the increase of TWEAK dose (Figure 4A)
We demonstrated that TWEAK induces cytoplasmic cellular inhibitor of apoptosis 1 (cIAP1) importation and receptor-interacting serine/threonine-protein kinase 1 (RIP1) ubiquitination in SCC-13 cells, accompanied by activation of canonical nuclear factor kappa B (NF-κB) signals
Summary
Tumor necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK) is a soluble cytokine and belongs to the members of the TNF superfamily. TWEAK acts through engaging its cognate receptor, fibroblast growth factor-inducible 14 (Fn14). Many studies demonstrated that the TWEAK/Fn14 signaling pathway participates in the progression and metastasis of cancers [1,2,3]. TWEAK is mainly synthesized by infiltrating inflammatory cells including macrophages, which accumulate in cancer tissues [4]. Both TWEAK and Fn14 are overexpressed in various malignancies though they have very low levels in normal tissues [2]. TWEAK/Fn14 signals are believed to contribute to the development of cancers through enhancing the proliferation, invasion and migration of cancer cells as well as the angiogenesis, inflammatory responses, and morphogenesis of non-cancer cells [2]. Targeting of the TWEAK/Fn14 molecules may prevent the progression of cancers and prolong the survival of murine cancer model [5, 6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
