Cisplatin promotes pyroptosis of gastric cancer cells by activating GSDME

According to studies, numerous chemotherapeutic drugs can facilitate programmed cell death via pyroptosis. Clarifying the mechanism by which cisplatin kills gastric cancer cells is crucial for enhancing gastric cancer’s sensitivity to chemotherapy and elucidating the mechanism of drug resistance in gastric cancer. The differentially expressed genes following cisplatin treatment were identified using second-generation sequencing technology. Bioinformatics was used to investigate the functional enrichment of differentially expressed genes and core genes in tumor cells killed by cisplatin. Cox regression analyses were used to examine the pyroptosis core genes that worked as independent prognostic factors for patients with gastric cancer. The expression of core genes in gastric cancer cells was silenced by siRNA, and the changes in the proliferation of gastric cancer cells were observed. The expression of related genes and the survival of gastric cancer cells after the addition of cisplatin were observed. The second-generation sequencing, RT-PCR and Western blotting showed that the pyroptosis core gene was significantly highly expressed after cisplatin treatment. The results of differential gene enrichment of cisplatin-treated gastric cancer cells showed that differential genes were mainly concentrated in biological processes and signaling pathways related to pyroptosis. GSDME protein is highly expressed after cisplatin treatment, and it is also a poor prognostic factor for gastric cancer patients and an independent prognostic factor. After the same dose of cisplatin treatment, the survival rate of siGSDME gastric cancer cells was significantly higher than that of GSDME regular expression gastric cancer cells. After acting on gastric cancer cells, cisplatin triggers pyroptosis by stimulating the activation of genes such as GSDME, resulting in the death of gastric cancer cells. GSDME is an independent prognostic factor for gastric cancer patients and is significantly linked with a shorter OS. In gastric cancer cells, silencing GSDME can substantially reduce cisplatin’s cytotoxicity. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by The 2021 Central-Guided Local Science and Technology Development Found (ZYYDDFFZZJ-1); Gansu Key Laboratory of Molecular Diagnosis and Precision Treatment of Surgical Tumors (18JR2RA033); Key Laboratory of Gastrointestinal Cancer Diagnosis and Treatment of National Health Commission (2019PT320005); Key Talent Project of Gansu Province of the Organization Department of Gansu Provincial Party Committee (2020RCXM076); Lanzhou COVID-19 prevention and control technology research project (2020-XG-1); Lanzhou talent innovation and entrepreneurship Project (2016-RC-56); Young Science and Technology Talent Support Project of Gansu Association for Science and Technology（GXH202220530-17）; The 2022 Master/Doctor/Postdoctoral program of NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor（NHCDP2022024） and Gansu Provincial Youth Science and Technology Fund Program (21JR7RA642). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The datasets analyzed during the current study are available in TCGA (https://portal.gdc.cancer.gov/), Gene Expression Profiling Interactive Analysis 2 (http://gepia2.cancer-pku.cn/), Kaplan Meier plotter portal (https://kmplot.com/analysis/), GEO database (https://www.ncbi.nlm.nih.gov/), The Molecular Signatures Database (https://www.gsea-msigdb.org/gsea/msigdb), and The Human Protein Atlas (https://www.proteinatlas.org/). This study was approved by the Medical Ethics Association of Gansu Provincial People's Hospital, ethical number: 2022316 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes * Abbreviation : GSDME : Gasdermin E GSDMD : Gasdermin D IL-6 : Interleukin-6 CASP1 : caspase-1 IC50 : Half inhibitory concentration TCGA : The Cancer Genome Atlas Program STAD : Stomach adenocarcinoma GO : Gene Ontology KEGG : Kyoto Encyclopedia of Genes and Genomes OS : overall survival FP : free progression PPS : post progression survival IPS : Immunophenoscore Bcl-2 : B-Cell CLL/Lymphoma 2 CASP3 : caspase-3 PARP : Poly(ADP-Ribose) Polymerase IL-1 beta : Interleukin-1beta