RESUMEN
Cuproptosis, a newly discovered programmed cell death induced by copper ions, is associated with the progression and drug resistance of various tumors. Docetaxel plays a vital role as a first-line chemotherapeutic agent for advanced prostate cancer; however, most patients end up with prostate cancer progression because of inherent or acquired resistance. Herein, we examined the role of cuproptosis in the chemotherapeutic resistance of prostate cancer to docetaxel. We treated prostate cancer cell lines with elesclomol-CuCl2 , as well as with docetaxel. We performed analyses of CCK8, colony formation tests, cell cycle flow assay, transmission electron microscopy, and mTOR signaling in treated cells, and treated a xenograft prostate cancer model with elesclomol-CuCl2 and docetaxel in vivo, and performed immunohistochemistry and Western blotting analysis in treated tumors. We found that elesclomol-CuCl2 could promote cell death and enhance chemosensitivity to docetaxel. Elesclomol-CuCl2 induced cell death and inhibited the growth of prostate cancer cells relying on copper ions-induced cuproptosis, not elesclomol. In addition, dihydrolipoamide S-acetyltransferase (DLAT) was involved in cuproptosis-enhanced drug sensitivity to docetaxel. Mechanistically, upregulated DLAT by cuproptosis inhibited autophagy, promoted G2/M phase retention of cells, and enhanced the sensitivity to docetaxel chemotherapy in vitro and in vivo via the mTOR signaling pathway. Our findings demonstrated that the cuproptosis-regulated DLAT/mTOR pathway inhibited autophagy and promoted cells in G2/M phase retention, thus enhancing the chemosensitivity to docetaxel. This discovery may provide an effective therapeutic option for treating advanced prostate cancer by inhibiting the chemotherapeutic resistance to docetaxel.
Asunto(s)
Cobre , Neoplasias de la Próstata , Masculino , Humanos , Docetaxel/farmacología , Docetaxel/uso terapéutico , Acetiltransferasa de Residuos Dihidrolipoil-Lisina/farmacología , Cobre/farmacología , Taxoides/farmacología , Taxoides/uso terapéutico , Neoplasias de la Próstata/metabolismo , Serina-Treonina Quinasas TOR , Apoptosis , Autofagia , Línea Celular TumoralRESUMEN
The high immune infiltration and heterogeneity of the microenvironment in clear cell renal cell carcinoma (ccRCC) result in the variability of prognosis and clinical response. While PANoptosis has strong immunogenicity and is worthy of further study. In this study, data from The Cancer Genome Atlas database was used to obtain immune-related PANoptosis lncRNAs with prognostic value. Subsequently, the role of these lncRNAs in cancer immunity, progression and the therapeutic response was analyzed, and a new prediction model was constructed. Additionally, we further explored the biological value of PANoptosis-related lncRNAs using single-cell data from the Gene Expression Omnibus database. PANoptosis-associated lncRNAs were significantly associated with clinical outcome, immune infiltration, antigen presentation and treatment response in ccRCC. Notably, the risk model, which is based on these immune-related PANoptosis lncRNAs, showed good predictive performance. Subsequent studies on LINC00944 and LINC02611 revealed their high expression in ccRCC and significant correlation with cancer cell migration and invasion. Single-cell sequencing further validated these results and revealed the potential association between LINC00944 and T-cell infiltration and programmed cell death. In conclusion, this study identified the role of immune-related PANoptosis lncRNAs in ccRCC and provided a new risk stratification approach. Furthermore, it highlights the potential of LINC00944 as a prognostic biomarker.
Asunto(s)
Carcinoma de Células Renales , Carcinoma , Neoplasias Renales , ARN Largo no Codificante , Humanos , Carcinoma de Células Renales/genética , ARN Largo no Codificante/genética , Transcriptoma , Neoplasias Renales/genética , Pronóstico , Microambiente Tumoral/genéticaRESUMEN
OBJECTIVE: Prostate adenocarcinoma (PRAD) is one of the most common cancers, with high morbidity and mortality. Triggering receptors expressed on myeloid cells 2 (TREM2) is upregulated in various malignancies, however its effect on PRAD remains unknown. This study aimed to investigate the prognostic value of TREM2 in PRAD. METHODS: PRAD samples were collected from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), Oncomine, and the Human Protein Atlas (HPA) to analyze the differences in TREM2 expression between normal and tumor tissues. The influence of TREM2 on the clinicopathological characteristics and its prognostic value were evaluated using the Kaplan-Meier curve, Cox regression analysis, ROC (receiver operating characteristic) plot, and nomogram. Gene Ontology (GO), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) were conducted to screen biological functions and pathways. The relationship between TREM2 and tumor microenvironment (TME) characteristics was explored. The TREM2 expression in PRAD specimens and cell lines was assessed by immunohistochemistry staining and western blot. TREM2-specific siRNAs were used to evaluate the effects of TREM2 on cell function. RESULTS: TREM2 was upregulated and positively associated with poor clinicopathologic characteristics. Overexpression of TREM2 is an independent biomarker for the prognosis of PFI (progression-free interval). Moreover, TREM2 expression was positively correlated with various TME characteristics. Knockdown of TREM2 inhibited the migration of PRAD cell lines via the PI3K/AKT axis. CONCLUSION: High TREM2 expression may represent a novel diagnostic and prognostic biomarker and serve as a potential target gene for PRAD therapy.
RESUMEN
Background: TCIRG1, also known as V-ATPase-a3, is critical for cellular life activities through its dependent acidification. Prior to the present research, its relationship with prognostic and tumor immunity in clear cell renal cell carcinoma (ccRCC) had not yet been investigated. Methods: We assessed TCIRG1 expression in normal and tumor tissues using data from TCGA, GEO, GTEX, and IHC. We also analyzed the relationship between TCIRG1 and somatic mutations, TMB, DNA methylation, cancer stemness, and immune infiltration. We evaluated the relevance of TCIRG1 to immunotherapy and potential drugs. Finally, we explored the effect of TCIRG1 knockdown on tumor cells. Results: TCIRG1 was overexpressed in tumor tissue and predicted a significantly unfavorable clinical outcome. High TCIRG1 expression may be associated with fewer PBRM1 and more BAP1 mutations and may reduce DNA methylation, thus leading to a poor prognosis. TCIRG1 was strongly associated with CD8+ T-cell, Treg, and CD4+ T-cell infiltration. Moreover, TCIRG1 was positively correlated with TIDE scores and many drug sensitivities. Finally, experiments showed that the knockdown of TCIRG1 inhibited the migration of ccRCC cells. Conclusions: TCIRG1 may have great potential in identifying prognostic and immunomodulatory mechanisms in tumor patients and may provide a new therapeutic strategy for ccRCC.