RESUMEN
PURPOSE: To explore the mechanisms of radiotherapy resistance and search for prognostic biomarkers for prostate cancer. METHODS: The GSE192817 and TCGA PRAD datasets were selected and downloaded from the GEO and UCSC Xena databases. Differential expression and functional annotation analyses were applied to 52 tumour cell samples from GSE192817. Then, the ssGSEA or GSVA algorithms were applied to quantitatively score the biological functional activity of samples in the GSE192817 and TCGA PRAD datasets, combined with specific gene sets collected from the Molecular Signatures Database (MSigDB). Subsequently, the Wilcoxon rank-sum test was used to compare the differences in ssGSEA or GSVA scores among cell types or PRAD patients. Moreover, radiotherapy resistance-associated gene screening was performed on DU145 and PC3 cells (prostate cancer cells), and survival analysis was used to evaluate the efficacy of these genes for predicting the prognosis of PRAD patients. RESULTS: A total of 114 genes that were differentially expressed in more than two different cancer cell types and associated with either sham surgery or radiotherapy treatment (X-ray or photon irradiation) were detected in cancer cells from GSE192817. Comparison of DNA damage-related ssGSEA scores between sham surgery and radiotherapy treatment in prostate cancer cells (DU145 and PC3) showed that photon irradiation was potentially more effective than X-ray treatment. In the TCGA PRAD dataset, patients treated with radiotherapy had much higher "GOBP_CELLULAR_RESPONSE_TO_DNA_DAMAGE_STIMULUS", "GOBP_G2_DNA_DAMAGE_CHECKPOINT" and "GOBP_INTRA_S_DNA_DAMAGE_CHECKPOINT" GSVA scores, and the Wilcoxon rank-sum test p values were 0.0005, 0.0062 and 0.0800, respectively. Furthermore, SRXN1 was upregulated in DU145 cells (resistant to X-ray irradiation compared to PC3 cells) after radiotherapy treatment, and low SRXN1 expression in patients was beneficial to radiotherapy outcomes. The log-rank test p value for PFS was 0.0072. CONCLUSIONS: Radiotherapy can damage DNA and induce oxidative stress to kill tumour cells. In this study, we found that SRXN1, as an antioxidative stress gene, plays an important role in radiotherapy for prostate cancer treatment, and this gene is also a potential biomarker for predicting the prognosis of patients treated with radiotherapy.
Asunto(s)
Neoplasias de la Próstata , Masculino , Humanos , Pronóstico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/radioterapia , Próstata , Algoritmos , Línea Celular , Oxidorreductasas actuantes sobre Donantes de Grupos SulfuroRESUMEN
BACKGROUND: Cisplatin induced nephrotoxicity is primarily caused by ROS (Reactive Oxygen Species) induced proximal tubular cell death. NADPH oxidase is major source of ROS production by cisplatin. Here, we reported that pharmacological inhibition of NADPH oxidase by acetovanillone (obtained from medicinal herb Picrorhiza kurroa) led to reduced cisplatin nephrotoxicity in mice. METHODS: In this study we used various molecular biology and biochemistry methods a clinically relevant model of nephropathy, induced by an important chemotherapeutic drug cisplatin. RESULTS: Cisplatin-induced nephrotoxicity was evident by histological damage from loss of the tubular structure. The damage was also marked by the increase in blood urea nitrogen, creatinine, protein nitration as well as cell death markers such as caspase 3/7 activity and DNA fragmentation. Tubular cell death by cisplatin led to pro-inflammatory response by production of TNFα and IL1ß followed by leukocyte/neutrophil infiltration which resulted in new wave of ROS involving more NADPH oxidases. Cisplatin-induced markers of kidney damage such as oxidative stress, cell death, inflammatory cytokine production and nephrotoxicity were attenuated by acetovanillone. In addition to that, acetovanillone enhanced cancer cell killing efficacy of cisplatin. CONCLUSION: Thus, pharmacological inhibition of NADPH oxidase can be protective for cisplatin-induced nephrotoxicity in mice.