5-Fluorouracil enhances the chemosensitivity of gastric cancer to TRAIL via inhibition of the MAPK pathway

Li, Hui; Lv, Jing; Guo, Jing; Wang, Shasha; Liu, Shihai; Ma, Yuanyuan; Liang, Zhiwei; Wang, Yunyun; Qi, Weiwei; Qiu, Wensheng

doi:10.21203/rs.3.rs-44290/v1

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“…A previous GC study showed that cisatracurium besilate enhanced TRAIL-induced GC apoptosis through tumor protein 53 signaling (23). Li et al found that 5-fluorouracil (5-FU) enhanced the chemosensitivity of GC to TRAIL by inhibiting the mitogen-activated protein kinase (MAPK) pathway (24). Periplocin upregulated DRs by activating the extracellular signal-regulated protein kinases1/2 pathway (25).…”

Section: Discussionmentioning

confidence: 99%

Decitabine enhances the tumoricidal potential of TRAIL via the epigenetic regulation of death receptor 4 in gastric cancer

Niu

Zhu

et al. 2022

J Gastrointest Oncol

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Background: Deoxyribonucleic acid (DNA) methyltransferase inhibitors, such as decitabine, have made great advances in cancer therapy as combinational drugs. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has an obvious anti-tumor effect; however, some gastric cancer (GC) cells are resistant to TRAIL-induced cell death. This study sought to explore the synergistic anti-tumor effect of TRAIL and decitabine, and the potential synergetic mechanism. Methods: The cell growth inhibition effect was monitored by the IncuCyte ZOOM Live-Cell Analysis System, and cell viability was determined by Cell Counting Kit-8 assays. Apoptosis was detected by Annexin V/Propidium Iodide double staining. Death receptor 4 (DR4) was knocked down by ribonucleic acid (RNA) interference, and the effect of DR4 deletion on TRAIL sensitivity was analyzed. Methylationspecific polymerase chain reaction (PCR) was applied to determine the methylation status of DR4. The messenger RNA (mRNA) and protein expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. The expression of the DRs on the cell membrane surfaces was analyzed by flow cytometry.Results: The combined use of decitabine and TRAIL synergistically inhibited cell growth in 2 TRAILresistant cell lines. Further, decitabine augmented TRAIL-induced apoptosis in a caspase-dependent manner.The co-application of decitabine and TRAIL facilitated the activation of caspase-7, -8, -9, and poly ADPribose polymerase (PARP). Notably, decitabine increased the expression of DR4 at the transcriptional and post-transcriptional levels. DR4 expression on the cell membrane surfaces was also upregulated after decitabine exposure. The depletion of DR4 by specific inhibitors attenuated TRAIL-induced apoptosis and weakened the synergistic effects of decitabine and TRAIL. In addition, DR4 gene presented methylation status in SNU-1 cells. The low mRNA and protein expression of DR4 were also detected in SNU-1 cells.Conclusions: Decitabine enhances the effect of TRAIL by inhibiting the growth and inducing the apoptosis of GC cells. This is achieved by the epigenetic modification of decitabine, which upregulates DR4. Decitabine may act as a sensitizing agent of TRAIL. The combined use of decitabine and TRAIL may provide a novel idea for GC treatment.

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Section: Discussionmentioning

confidence: 99%