2. Academic Validation
  3. Smac mimetic promotes TNF-α to induce apoptosis of gallbladder carcinoma cells

Smac mimetic promotes TNF-α to induce apoptosis of gallbladder carcinoma cells

  • Cell Signal. 2020 Aug;72:109654. doi: 10.1016/j.cellsig.2020.109654.
Mingyuan Chen 1,  Maotuan Huang 1,  Weihong Chen 1,  Xiaojie Jiang 2,  Wei Su 1,  Xiaoqian Wang 3,  Nanhong Tang 3,  Feifei She 4,  Yanling Chen 5
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fujian Medical University, Fuzhou, China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer and Key Laboratory of Tumour Microbiology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
  • 2 Department of Hepatobiliary Surgery, Affiliated Putian Hospital of Putian College, Fujian, China.
  • 3 Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fujian Medical University, Fuzhou, China.
  • 4 Key Laboratory of Ministry of Education for Gastrointestinal Cancer and Key Laboratory of Tumour Microbiology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. Electronic address: shefeifei@yeah.net.
  • 5 Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fujian Medical University, Fuzhou, China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer and Key Laboratory of Tumour Microbiology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. Electronic address: drchenyl@126.com.
PMID: 32334028 DOI: 10.1016/j.cellsig.2020.109654
Abstract

Gallbladder carcinoma has a high degree of malignancy. No effective treatment exists for patients with advanced tumors. The second mitochondria-derived activator of caspases (Smac) is the antagonist of the inhibitors of Apoptosis protein. Smac mimetics are a class of effective tumor-targeted drugs undergoing clinical trials. However, studies on the effect of Smac mimetics on gallbladder Cancer are unavailable. In this study, Smac mimetics can promote tumor necrosis factor-α (TNF-α) to inhibit the proliferation of gallbladder Cancer cells and activate the apoptotic pathway, thereby promoting the ubiquitination of Lys48 on Receptor interacting protein kinase-1 (RIPK1) and leading to proteasomal degradation that causes damage to RIPK1 protein integrity. The formation of complex I (RIPK1, tumor necrosis factor 1-associated death domain protein, and TNF receptor-associated factor 2) is inhibited. Then, nonubiquitinated RIPK1 binds with the Fas-associated death domain and Caspase-8 to form complex II and promotes the death receptor pathway of Apoptosis. Animal experiments further verify that TNF-α combined with Smac mimetics can inhibit the growth of transplanted tumors and induce the Apoptosis of transplanted tumor cells. This research provides a new direction for the targeted therapy of gallbladder Cancer.

Keywords

Apoptosis; Gallbladder carcinoma; RIPK1; Smac mimetic; TNF-α.

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