Depletion of death-associated protein-3 induces chemoresistance in gastric cancer cells through the β-catenin/LGR5/Bcl-2 axis

Abstract

Previously, we demonstrated that death-associated protein-3 (DAP3) loss drives chemoresistance in gastric cancer cells. In the present study, we aimed to determine the underlying molecular mechanism. The effect of DAP3 silencing on β-catenin signaling was assessed. The direct mediator of DAP3 silencing-induced chemoresistance was identified. Depletion of DAP3 stimulates nuclear accumulation of β-catenin and enhances β-catenin-dependent transcriptional activity in gastric cancer cells. However, the protein kinase B , , extracellular regulated protein kinase and signal transducer and activator of transcription 3 signaling pathways remain unaffected by DAP3 loss. We found that the downstream target gene LGR5 (leucine-rich G-protein coupled receptor 5) is upregulated in DAP3-depleted gastric cancer cells. Moreover, knockdown of LGR5 resensitizes DAP3-depleted gastric cancer cells to 5-fluorouracil (5-FU) and oxaliplatin. We also observed that ectopic expression of LGR5 reduces apoptosis in gastric cancer cells on treatment with 5-FU and oxaliplatin, which is accompanied by prevention of caspase-3 cleavage. The antiapoptotic protein Bcl-2 is identified as a key mediator of LGR5-induced apoptosis resistance in gastric cancer cells. The present findings indicate that DAP3 deficiency-induced chemoresistance in gastric cancer is at least partially mediated through the β-catenin/LGR5/Bcl-2 axis. Targeting LGR5 may provide a novel strategy to overcome chemoresistance in DAP3-deficient gastric cancer cells.

Expression of Death Associated Proteins DAP1 and DAP3 in Human Pancreatic Cancer

“…Reduced DAP3 was seen in aggressive and late stage tumours and in patients who developed metastasis and recurrence (15). The same trends were observed in gastric cancer (16,17).…”

“…This correlation is in contrast to that of DAP1, in that high levels of DAP1 are seen with a marginally longer survival. DAP3 expression and survival in pancreatic cancer was similarly reported in glioblastoma multiforme tumours (7) and in late stage thymomas (14), but is opposite to those reported in breast (15) and gastric cancer (16,17). Collectively, it is clear that DAP3 has prognostic value and is predictive of poor patient outcome.…”

MicroRNA-27a (miR-27a) in Solid Tumors: A Review Based on Mechanisms and Clinical Observations

“…Chemoresistance is frequently observed in most cancers, such as lung cancer and gastric cancer (89, 90). miR-27a has been reported to be associated with chemotherapy resistance in several cancers, while the mechanism of miR-27a in chemoresistance, despite several years of research, remains unclear (91).…”

Potential of Mitochondrial Ribosomal Genes as Cancer Biomarkers Demonstrated by Bioinformatics Results

“…In addition, MRPS23 has been identified as a driver of proliferation in luminal breast cancer, as supported by a series of in vitro and in vivo studies (54,55). The depletion of MRPS29 functions via the b-Catenin/Lgr5/Bcl-2 axis to induce drug resistance in gastric cancer cells (99). MRPL54, EZH2, PPARGC1A, and EIF2AK4 were identified as hub genes in bioinformatics analysis of hepatocellular carcinoma (HCC).…”