Downregulation of DcR3 sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis

Abstract

Decoy receptor 3 (DcR3) has been recently described as an antiapoptosis and prometastasis factor since it can competitively bind to FasL, TL1A, and LIGHT, and it is highly expressed in many malignant tumors. Downregulation of DcR3 can promote tumor cell apoptosis and inhibit metastasis. A previous study demonstrated that reduction of DcR3 could induce tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in pancreatic cancer cells. However, whether such an effect is seen in hepatocellular carcinoma (HCC) remains to be explored. This study was designed to investigate the sensitivity of HCC cells to TRAIL after silencing DcR3, and this was done by evaluating the expression of DcR3 in HCC cells and the effect on TRAIL-mediated apoptosis after downregulation of DcR3. Our data showed that DcR3 was highly expressed in HepG2, BEL-7402, Hep3B, Huh-7, MHCC97H, and SMCC7721 cell lines compared with normal liver cell line LO-2. Both HepG2 and BEL-7402 were tolerant to TRAIL-mediated apoptosis, and the tolerance was negatively correlated to the expression of DcR3. Silencing of DcR3 with shRNA and treatment with TRAIL induced obvious apoptosis in HepG2 and BEL-7402, with more cancer cells found in the G1 phase. SiDcR3 combined with TRAIL could induce activation of caspases-3, -8, and -9, raise the expression of the apoptotic protein Bax, and reduce the expression of antiapoptotic proteins (Bcl-2, Mcl-1, Bcl-XL, IAP-2, and survivin). Caspase-8 inhibitor Ac-IETD-CHO significantly decreased the activation of caspase cascade, indicating that the extrinsic pathway may have a vital role in the apoptotic events induced by SiDcR3/TRAIL. Furthermore, our results showed that the TRAIL death receptor 5 (DR5) was upregulated and that DR5 neutralizing antibody abrogated the effect of SiDcR3. Our results demonstrated that downregulation of DcR3 could enhance TRAIL-mediated apoptosis in HCC through the death receptor pathway. In the future, this might be useful as a clinical treatment method of liver cancer.

XB130 Knockdown Inhibits the Proliferation, Invasiveness, and Metastasis of Hepatocellular Carcinoma Cells and Sensitizes them to TRAIL-Induced Apoptosis

“…[ 38 39 40 ] Some studies confirmed that many tumor cells are resistant to TRAIL, including HCC cells. [ 41 42 ] It has previously been shown that activation of the PI3K/Akt pathway promotes tumor cell tolerance to TRAIL, whereas inhibition of this pathway can make tumor cells susceptible to TRAIL. [ 20 ] Because reduction of XB130 can inhibit the activation of PI3K/Akt, we explored whether XB130 contributes to the resistance to TRAIL by HCC.…”

Knockdown of miR-27a sensitizes colorectal cancer stem cells to TRAIL by promoting the formation of Apaf-1-caspase-9 complex

“…In TNF superfamily, the cytokine of TNF-related apoptosis-inducing ligand (TRAIL) is considered as a potential anti-tumor agent. Treatment with TRAIL effectively kills multiple cancer cells, such as hepatocellular carcinoma cells and colorectal cancer [ 11 , 12 ]. As TRAIL induces significant apoptosis selectively in tumor cells without influencing the function of normal cells, it has been tested in clinical trials for treatment of various cancers [ 13 ].…”

Anti‐oral cancer effects of triptolide by downregulation of DcR3 in vitro, in vivo, and in preclinical patient‐derived tumor xenograft model

“…Decoy receptor 3 (DcR3 or TNFRSF6B) is a soluble receptor belonging to the tumor necrosis factor receptor superfamily (TNFRSF) that binds competitively to other TNFSF members, such as Fas ligand (FasL/TNFSF6/ CD95L), 4 LIGHT (TNFSF14), 5 and TNF-like molecule 1A (TL1A/TNFSF15). 6 Upregulation of DcR3 was associated with poor prognosis in several malignancies [7][8][9][10][11][12][13][14][15][16] due to its effect on angiogenesis and the proliferation, invasion, and metastasis of tumor cells. [7][8][9][17][18][19] However, very few studies have explored the clinicopathological role of DcR3 in oral cancer.…”