PP2A promotes apoptosis and facilitates docetaxel sensitivity via the PP2A/p-eIF4B/XIAP signaling pathway in prostate cancer.

Serine/threonine protein phosphatase 2A (PP2A) is a protein that has a wide range of biological functions. As prostate cancer progresses from hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC), the expression level of PP2A has been found to decrease. The present study aimed to determine the roles that PP2A may play in prostate cancer and its association with the downstream factor, X-linked inhibitor of apoptosis (XIAP). First, the mRNA and protein expression levels of PP2A in LNCaP, DU145 and PC-3 prostate cancer cell lines were measured. Next, the population of PP2A heterodimers was increased using a PP2A agonist, DT061, in the DU145 and PC-3 cell lines. PP2A expression was then knocked down in the LNCaP cell line. Western blot analysis was performed to determine the association between PP2A, phosphorylated (p)-eukaryotic initiation factor 4B (eIF4B) and XIAP. The results revealed that following the increase in PP2A expression, the DU145 and PC-3 cell lines were more sensitive to docetaxel according to Cell Counting Kit-8 assays and had an increased apoptotic rate as assessed by flow cytometry. Conversely, following the transfection of small interfering (si)PP2A into the LNCaP cell line, the sensitivity to docetaxel decreased, as well as the apoptotic rate. In addition, following treatment with the PP2A agonist, DT061, PP2A expression was found to be significantly upregulated, while p-eIF4B and XIAP protein expression levels were significantly downregulated. By contrast, following the transfection of siPP2A into the LNCaP cell line, PP2A protein expression levels were found to be downregulated, while p-eIF4B and XIAP expression levels were significantly upregulated. In conclusion, by affecting the downstream factor XIAP, PP2A may play a key role in promoting apoptosis and facilitating docetaxel sensitivity in prostate cancer cell lines.

Starvation induced autophagy promotes the progression of bladder cancer by LDHA mediated metabolic reprogramming.

BACKGROUND: Aberrant autophagy and preternatural elevated glycolysis are prevalent in bladder cancer (BLCA) and are both related to malignant progression. However, the regulatory relationship between autophagy and glycolytic metabolism remains largely unknown. We imitated starvation conditions in the tumour microenvironment and found significantly increased levels of autophagy and aerobic glycolysis, which both regulated the progression of BLCA cells. We further explored the regulatory relationships and mechanisms between them. METHODS: We used immunoblotting, immunofluorescence and transmission electron microscopy to detect autophagy levels in BLCA cells under different treatments. Lactate and glucose concentration detection demonstrated changes in glycolysis. The expression of lactate dehydrogenase A (LDHA) was detected at the transcriptional and translational levels and was also silenced by small interfering RNA, and the effects on malignant progression were further tested. The underlying mechanisms of signalling pathways were evaluated by western blot, immunofluorescence and immunoprecipitation assays. RESULTS: Starvation induced autophagy, regulated glycolysis by upregulating the expression of LDHA and caused progressive changes in BLCA cells. Mechanistically, after starvation, the ubiquitination modification of Axin1 increased, and Axin1 combined with P62 was further degraded by the autophagy-lysosome pathway. Liberated ß-catenin nuclear translocation increased, binding with LEF1/TCF4 and promoting LDHA transcriptional expression. Additionally, high expression of LDHA was observed in cancer tissues and was positively related to progression. CONCLUSION: Our study demonstrated that starvation-induced autophagy modulates glucose metabolic reprogramming by enhancing Axin1 degradation and ß-catenin nuclear translocation in BLCA, which promotes the transcriptional expression of LDHA and further malignant progression.

SPHK1 contributes to cisplatin resistance in bladder cancer cells via the NONO/STAT3 axis.

Sphingosine­1­phosphate (S1P) serves an important role in various physiological and pathophysiological processes, including the regulation of cell apoptosis, proliferation and survival. Sphingosine kinase 1 (SPHK1) is a lipid kinase that phosphorylates sphingosine to generate S1P. S1P has been proven to be positively correlated with chemotherapy resistance in breast cancer, colorectal carcinoma and non­small cell lung cancer. However, whether SPHK1 is involved in the development of cisplatin resistance remains to be elucidated. The present study aimed to identify the association between SPHK1 and chemoresistance in bladder cancer cells and to explore the therapeutic implications in patients with bladder cancer. Bladder cancer cell proliferation and apoptosis were determined using Cell Counting Kit­8 assays and flow cytometry, respectively. Apoptosis­related proteins were detected via western blotting. The results revealed that SPHK1 was positively correlated with cisplatin resistance in bladder cancer cells, exhibiting an antiapoptotic effect that was reflected by the downregulation of apoptosis­related proteins (Bax and cleaved caspase­3) and the upregulation of an antiapoptotic protein (Bcl­2) in SPHK1­overexpression cell lines. Suppression of SPHK1 by small interfering RNA or FTY­720 significantly reversed the antiapoptotic effect. A potential mechanism underlying SPHK1­induced cisplatin resistance and apoptosis inhibition may be activation of STAT3 via binding non­POU domain containing octamer binding. In conclusion, the present study suggested that SPHK1 displayed significant antiapoptotic effects in cisplatin­based treatment, thus may serve as a potential novel therapeutic target for the treatment for bladder cancer.

A Glycolysis-Based Long Non-coding RNA Signature Accurately Predicts Prognosis in Renal Carcinoma Patients.

BACKGROUND: The prognosis of renal cell carcinoma (RCC) varies greatly among different risk groups, and the traditional indicators have limited effect in the identification of risk grade in patients with RCC. The purpose of our study is to explore a glycolysis-based long non-coding RNAs (lncRNAs) signature and verify its potential clinical significance in prognostic prediction of RCC patients. METHODS: In this study, RNA data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate cox regression displayed six significantly related lncRNAs (AC124854.1, AC078778.1, EMX2OS, DLGAP1-AS2, AC084876.1, and AC026401.3) which were utilized in construction of risk score by a formula. The accuracy of risk score was verified by a series of statistical methods such as receiver operating characteristic (ROC) curves, nomogram and Kaplan-Meier curves. Its potential clinical significance was excavated by gene enrichment analysis. RESULTS: Kaplan-Meier curves and ROC curves showed reliability of the risk score to predict the prognosis of RCC patients. Stratification analysis indicated that the risk score was independent predictor compare to other traditional clinical parameters. The clinical nomogram showed highly rigorous with index of 0.73 and precisely predicted 1-, 3-, and 5-year survival time of RCC patients. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene set enrichment analysis (GSEA) depicted the top ten correlated pathways in both high-risk group and low-risk group. There are 6 lncRNAs and 25 related mRNAs including 36 lncRNA-mRNA links in lncRNA-mRNA co-expression network. CONCLUSION: This research demonstrated that glycolysis-based lncRNAs possessed an important value in survival prediction of RCC patients, which would be a potential target for future treatment.

Identification of a Three-Glycolysis-Related lncRNA Signature Correlated With Prognosis and Metastasis in Clear Cell Renal Cell Carcinoma.

The clear cell renal cell carcinoma (ccRCC) is not only a malignant disease but also an energy metabolic disease, we aimed to identify a novel prognostic model based on glycolysis-related long non-coding RNA (lncRNAs) and explore its mechanisms. With the use of Pearson correlation analysis between the glycolysis-related differentially expressed genes and lncRNAs from The Cancer Genome Atlas (TCGA) dataset, we identified three glycolysis-related lncRNAs and successfully constructed a prognostic model based on their expression. The diagnostic efficacy and the clinically predictive capacity of the signature were evaluated by univariate and multivariate Cox analyses, Kaplan-Meier survival analysis, and principal component analysis (PCA). The glycolysis-related lncRNA signature was constructed based on the expressions of AC009084.1, AC156455.1, and LINC00342. Patients were grouped into high- or low-risk groups according to risk score demonstrated significant differences in overall survival (OS) period, which were validated by patients with ccRCC from the International Cancer Genome Consortium (ICGC) database. Univariate Cox analyses, multivariate Cox analyses, and constructed nomogram-confirmed risk score based on our signature were independent prognosis predictors. The CIBERSORT algorithms demonstrated significant correlations between three-glycolysis-related lncRNAs and the tumor microenvironment (TME) components. Functional enrichment analysis demonstrated potential pathways and processes correlated with the risk model. Clinical samples validated expression levels of three-glycolysis-related lncRNAs, and LINC00342 demonstrated the most significant aberrant expression. in vitro, the general overexpression of LINC00342 was detected in ccRCC cells. After silencing LINC00342, the aberrant glycolytic levels and migration abilities in 786-O cells were decreased significantly, which might be explained by suppressed Wnt/ß-catenin signaling pathway and reversed Epithelial mesenchymal transformation (EMT) process. Collectively, our research identified a novel three-glycolysis-related lncRNA signature as a promising model for generating accurate prognoses for patients with ccRCC, and silencing lncRNA LINC00342 from the signature could partly inhibit the glycolysis level and migration of ccRCC cells.