GSDME Increases Chemotherapeutic Drug Sensitivity by Inducing Pyroptosis in Retinoblastoma Cells

Abstract

Chemotherapy is an important part of retinoblastoma (RB) treatment. However, the development of drug resistance increases the likelihood of treatment failure. Therefore, increasing the sensitivity of chemotherapeutic drugs is very important. Recent research has explored the relationship between the expression level of gasdermin E (GSDME) and drug sensitivity in RB. Our study found that GSDME expression was significantly reduced in human RB tissues and cell lines. Downregulation of GSDME expression reduced the sensitivity of cells to chemotherapeutic drugs. Decitabine treatment and transfection with GSDME-overexpressing lentivirus (LV-GSDME) upregulated GSDME expression in Y79 and WERI-RB-1 cell lines. The half maximal inhibitory concentrations (IC50) for carboplatin-induced cell death were significantly reduced. Low-dose carboplatin could achieve the IC50, and no significant difference was found in the production of prodeath-activating proteins, but the mode of cell death changed from apoptosis to pyroptosis. Increased GSDME expression can reduce the required dose of chemotherapeutic drugs. After inhibition of caspase-3 activation, the IC50 of carboplatin-induced cell death was significantly increased in cells with high GSDME expression, and the method of cell death switched from pyroptosis to apoptosis, which increased the concentration of chemotherapeutic drugs. Furthermore, the sensitivity of cells to carboplatin was reduced. The in vivo xenograft tumor model further confirmed that GSDME upregulation could promote carboplatin-induced tumor cell death. Therefore, the sensitivity of cells to chemotherapeutic drugs can be predicted by detecting the GSDME expression level, and we used pyroptosis induction as a new method for promoting tumor death.

Evaluation of the antibacterial, antibiofilm, and anti-virulence effects of acetic acid and the related mechanisms on colistin-resistant Pseudomonas aeruginosa

“…To measure the disruption of the inner membrane barrier function, the membrane integrity dye propidium iodide (PI) was used. PI is a nucleic acid dye that cannot pass through normal membranes owing to their barrier action, but it can dye the nucleus red in necrotic cells with altered membrane permeability [ 32 ]. A graded series of AA concentrations (1 × , 1/2 × , 1/4 × , 1/8 × , 1/16 × MIC) were prepared.…”

A novel risk score model based on pyroptosis-related genes for predicting survival and immunogenic landscape in hepatocellular carcinoma

“…Previous studies have shown that GSDME is downregulated in some human cancers and might act as a tumor suppressor [ 39 , 40 ]. The DNA methylase inhibitor decitabine (5-aza-2'-deoxycytosine) could downregulate the expression of GSDME, thereby preventing the proliferation and colony formation ability of melanoma, gastric cancer and CRC cells, and may reduce the invasive ability of breast cancer cells [ 41 ]. In addition, GSDME is associated with etoposide resistance [ 42 ].…”

Role of pyroptosis in the pathogenesis and treatment of diseases

“… 227 , 228 , 229 Meanwhile, pyroptosis occurs in almost all the type of cancer and shows a double‐edged sword effect to cancers, which could either enhance or restrain tumorigenesis. 230 , 231 , 232 , 233 Therefore, we need to deeply explore the specific mechanism of pyroptosis and tumor progression to provide evidence for tumor prevention and treatment (Table 4 ).…”

“…Particularly, pyroptosis induces inflammatory cytokines release, such as IL‐1 and IL‐18, which could induce an inflammatory environment to increase tumor infiltration and promote the likelihood of tumorigenesis and metastasis 227–229 . Meanwhile, pyroptosis occurs in almost all the type of cancer and shows a double‐edged sword effect to cancers, which could either enhance or restrain tumorigenesis 230–233 . Therefore, we need to deeply explore the specific mechanism of pyroptosis and tumor progression to provide evidence for tumor prevention and treatment (Table 4).…”