Epirubicin enhances TRAIL-induced apoptosis in gastric cancer cells by promoting death receptor clustering in lipid rafts

Xu, Ling; Qu, Xiujuan; Luo, Ying; Zhang, Ye; Liu, Jing; Qu, Junle; Zhang, Lingyun; Liu, Yunpeng

doi:10.3892/mmr.2011.439

Cited by 15 publications

(13 citation statements)

References 20 publications

(21 reference statements)

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“…Both Epirubicin and Oxaliplatin can enhance TRAIL-induced apoptosis in gastric cancer cells by regulating death receptors (Xu et al, 2009; Xu et al, 2011). We have shown here that H72 increased the expression of both DR4 and DR5 expression in gastric cancer cells.…”

Section: Discussionmentioning

confidence: 99%

A new brominated chalcone derivative suppresses the growth of gastric cancer cells in vitro and in vivo involving ROS mediated up-regulation of DR5 and 4 expression and apoptosis

Zhang

et al. 2016

Toxicology and Applied Pharmacology

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A new series of 20 brominated chalcone derivatives were designed, synthesized, and investigated for their effects against the growth of four cancer cell lines (EC109, SKNSH, HepG2, MGC803). Among them, compound 19 which given chemical name of H72, was the most potent one on gastric cancer cell lines (i.e. MGC803, HGC27, SGC7901) with IC50s ranged from 3.57 to 5.61 μM. H72 exhibited less cytotoxicity to non-malignant gastric epithelial cells GES-1. H72 treatment of MGC803 and HGC27 induced generation of reactive oxygen species (ROS) leading to activation of caspase 9/3 cascade and mitochondria mediated apoptosis. H72 also up-regulated the expression of DR5, DR4 and BimEL, and down-regulated the expression of Bid, Bcl-xL, and XIAP. N-acetyl cysteine (NAC), a ROS scavenger completely blocked these effects of H72 in MGC803 cells. Intraperitoneal administration of H72 significantly inhibited the growth of MGC803 cells in vivo in a xenograft mouse model without observed toxicity. These results indicated that H72 is a lead brominated chalcone derivate and deserves further investigation for prevention and treatment of gastric cancer.

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Section: Discussionmentioning

confidence: 99%

A new brominated chalcone derivative suppresses the growth of gastric cancer cells in vitro and in vivo involving ROS mediated up-regulation of DR5 and 4 expression and apoptosis

Zhang

et al. 2016

Toxicology and Applied Pharmacology

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“…At variance, chemotherapic drugs bolstering TRAIL receptor recruitment into lipid rafts, for example, epirubicin, 24 cisplatin 25 or perifosine and edelfosine 13 significantly increased TRAIL sensitivity, suggesting that the combination of these drugs with TRAIL might offer a novel therapeutic strategy for cancer. In line with this hypothesis, some recent literature insight proposes the use of agents that modify the composition and structure of lipid membranes as anticancer drugs.…”

Section: Discussionmentioning

confidence: 99%

Constitutive localization of DR4 in lipid rafts is mandatory for TRAIL-induced apoptosis in B-cell hematologic malignancies

et al. 2013

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) acts as an apoptosis inducer for cancer cells sparing non-tumor cell targets. However, several phase I/II clinical trials have shown limited benefits of this molecule. In the present work, we investigated whether cell susceptibility to TRAIL ligation could be due to the presence of TRAIL death receptors (DRs) 4 and 5 in membrane microdomains called lipid rafts. We performed a series of analyses, either by biochemical methods or fluorescence resonance energy transfer (FRET) technique, on normal cells (i.e. lymphocytes, fibroblasts, endothelial cells), on a panel of human cancer B-cell lines as well as on CD19+ lymphocytes from patients with B-chronic lymphocytic leukemia, treated with different TRAIL ligands, that is, recombinant soluble TRAIL, specific agonistic antibodies to DR4 and DR5, or CD34+ TRAIL-armed cells. Irrespective to the expression levels of DRs, a molecular interaction between ganglioside GM3, abundant in lymphoid cells, and DR4 was detected. This association was negligible in all non-transformed cells and was strictly related to TRAIL susceptibility of cancer cells. Interestingly, lipid raft disruptor methyl-beta-cyclodextrin abrogated this susceptibility, whereas the chemotherapic drug perifosine, which induced the recruitment of TRAIL into lipid microdomains, improved TRAIL-induced apoptosis. Accordingly, in ex vivo samples from patients with B-chronic lymphocytic leukemia, the constitutive embedding of DR4 in lipid microdomains was associated per se with cell death susceptibility, whereas its exclusion was associated with TRAIL resistance. These results provide a key mechanism for TRAIL sensitivity in B-cell malignances: the association, within lipid microdomains, of DR4 but not DR5, with a specific ganglioside, that is the monosialoganglioside GM3. On these bases we suggest that lipid microdomains could exert a catalytic role for DR4-mediated cell death and that an ex vivo quantitative FRET analysis could be predictive of cancer cell sensitivity to TRAIL.

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“…In the DISC, caspase‐8 is activated and cleaved to subsequently initiate apoptosis (Dickens et al ., 2012). Our work and others have shown that gastric cancer cells are not sensitive to TRAIL (Fuentes et al ., 2015; Xu et al ., 2011, 2013a,b). However, the underlying mechanism has not been determined.…”

Section: Introductionmentioning

confidence: 99%

DR5‐Cbl‐b/c‐Cbl‐TRAF2 complex inhibits TRAIL‐induced apoptosis by promoting TRAF2‐mediated polyubiquitination of caspase‐8 in gastric cancer cells

Zhang

et al. 2017

Molecular Oncology

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Ubiquitination of caspase‐8 regulates TNF‐related apoptosis‐inducing ligand (TRAIL) sensitivity in cancer cells, and the preligand assembly complex plays a role in caspase‐8 polyubiquitination. However, whether such a complex exists in gastric cancer cells and its role in TRAIL‐triggered apoptosis is unclear. In this study, DR5, casitas B‐lineage lymphoma‐b (Cbl‐b)/c‐Cbl, and TRAF2 formed a complex in TRAIL‐resistant gastric cancer cells, and Cbl‐b and c‐Cbl were the critical adaptors linking DR5 and TRAF2. Treatment with TRAIL induced caspase‐8 translocation into the DR5‐Cbl‐b/c‐Cbl‐TRAF2 complex to interact with TRAF2, which then mediated the K48‐linked polyubiquitination of caspase‐8. The proteasome inhibitor bortezomib markedly enriched the p43/41 products of caspase‐8 activated by TRAIL, indicating proteasomal degradation of caspase‐8. Moreover, TRAF2 knockdown prevented the polyubiquitination of caspase‐8 and thus increased TRAIL sensitivity. In addition, the inhibition of Cbl‐b or c‐Cbl expression and overexpression of miR‐141 targeting Cbl‐b and c‐Cbl partially reversed TRAIL resistance by inhibiting the interaction between TRAF2 and caspase‐8 and the subsequent polyubiquitination of caspase‐8. These results indicate that the DR5‐Cbl‐b/c‐Cbl‐TRAF2 complex inhibited TRAIL‐induced apoptosis by promoting TRAF2‐mediated polyubiquitination of caspase‐8 in gastric cancer cells.

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Epirubicin enhances TRAIL-induced apoptosis in gastric cancer cells by promoting death receptor clustering in lipid rafts

Cited by 15 publications

References 20 publications

A new brominated chalcone derivative suppresses the growth of gastric cancer cells in vitro and in vivo involving ROS mediated up-regulation of DR5 and 4 expression and apoptosis

A new brominated chalcone derivative suppresses the growth of gastric cancer cells in vitro and in vivo involving ROS mediated up-regulation of DR5 and 4 expression and apoptosis

Constitutive localization of DR4 in lipid rafts is mandatory for TRAIL-induced apoptosis in B-cell hematologic malignancies

DR5‐Cbl‐b/c‐Cbl‐TRAF2 complex inhibits TRAIL‐induced apoptosis by promoting TRAF2‐mediated polyubiquitination of caspase‐8 in gastric cancer cells

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