Dataset Information

Celastrol Attenuates Lipid Accumulation and Stemness of Clear Cell Renal Cell Carcinoma via CAV-1/LOX-1 Pathway.

ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is characterized by abnormal lipid accumulation. Celastrol is a pentacyclic triterpene extracted from Tripterygium wilfordii Hook F with anti-cancer activity. In the present study, the anticancer effects of celastrol on ccRCC and the underlying mechanisms were studied. Patients with reduced high density lipoprotein (HDL) and elevated levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL) was found to have higher risk of ccRCC. In ccRCC clinical samples and cell lines, caveolin-1 (CAV-1) was highly expressed. CAV-1 was identified as a potential prognostic biomarker for ccRCC. Celastrol inhibited tumor growth and decreased lipid deposition promoted by high-fat diet in vivo. Celastrol reduced lipid accumulation and caveolae abundance, inhibited the binding of CAV-1 and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in ccRCC cells. Furthermore, celastrol attenuated stemness through blocking Wnt/β-catenin pathway after knockdown of CAV-1 and LOX-1. Therefore, the findings suggest that celastrol may be a promising active ingredient from traditional Chinese medicine for anti-cancer therapy.

SUBMITTER: Zhang CJ

PROVIDER: S-EPMC8085775 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Celastrol Attenuates Lipid Accumulation and Stemness of Clear Cell Renal Cell Carcinoma via CAV-1/LOX-1 Pathway.

Zhang Chan-Juan CJ Zhu Neng N Wang Yu-Xiang YX Liu Le-Ping LP Zhao Tan-Jun TJ Wu Hong-Tao HT Liao Duan-Fang DF Qin Li L

Frontiers in pharmacology 20210416

Clear cell renal cell carcinoma (ccRCC) is characterized by abnormal lipid accumulation. Celastrol is a pentacyclic triterpene extracted from Tripterygium wilfordii Hook F with anti-cancer activity. In the present study, the anticancer effects of celastrol on ccRCC and the underlying mechanisms were studied. Patients with reduced high density lipoprotein (HDL) and elevated levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL) was found to have higher risk of ccRCC. I ...[more]

PMID: 33935779

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Project description:Celastrol is a triterpene derived from the traditional Chinese medicine Tripterygium wilfordii Hook f, which displays potential anticancer activity. In the present study, we investigated the anticancer effects of celastrol against clear cell renal cell carcinoma (ccRCC) and the underlying mechanisms. Using Cancer Genome Atlas (TCGA) database and genotype-tissue expression (GTEx) database we conducted a bioinformatics analysis, which showed that the mRNA levels of liver-X receptors α (LXRα) and ATP-binding cassette transporter A1 (ABCA1) in ccRCC tissues were significantly lower than those in adjacent normal tissues. This result was confirmed by immunoblotting analysis of 4 ccRCC clinical specimens, which showed that the protein expression of LXRα and ABCA1 was downregulated. Similar results were obtained in a panel of ccRCC cell lines (786-O, A498, SN12C, and OS-RC-2). In 786-O and SN12C cells, treatment with celastrol (0.25-2.0 μM) concentration-dependently inhibited the cell proliferation, migration, and invasion as well as the epithelial-mesenchymal transition (EMT) process. Furthermore, we demonstrated that celastrol inhibited the invasion of 786-O cells through reducing lipid accumulation; celastrol concentration-dependently promoted autophagy to reduce lipid storage. Moreover, we revealed that celastrol dramatically activated LXRα signaling, and degraded lipid droplets by inducing lipophagy in 786-O cells. Finally, celastrol promoted cholesterol efflux from 786-O cells via ABCA1. In high-fat diet-promoted ccRCC cell line 786-O xenograft model, administration of celastrol (0.25, 0.5, 1.0 mg·kg-1·d-1, for 4 weeks, i.p.) dose-dependently inhibited the tumor growth with upregulated LXRα and ABCA1 protein in tumor tissue. In conclusion, this study reveals that celastrol triggers lipophagy in ccRCC by activating LXRα, promotes ABCA1-mediated cholesterol efflux, suppresses EMT progress, and ultimately inhibits cell proliferation, migration, and invasion as well as tumor growth. Thus, our study provides evidence that celastrol can be used as a lipid metabolism-based anticancer therapeutic approach.

Project description:BackgroudCancer stemness is associated with metastases in kidney renal clear cell carcinoma (KIRC) and negatively correlates with immune infiltrates. Recent stemness evaluation methods based on the absolute expression have been proposed to reveal the relationship between stemness and cancer. However, we found that existing methods do not perform well in assessing the stemness of KIRC patients, and they overlooked the impact of alternative splicing. Alternative splicing not only progresses during the differentiation of stem cells, but also changes during the acquisition of the stemness features of cancer stem cells. There is an urgent need for a new method to predict KIRC-specific stemness more accurately, so as to provide help in selecting treatment options.MethodsThe corresponding RNA-Seq data were obtained from the The Cancer Genome Atlas (TCGA) data portal. We also downloaded stem cell RNA sequence data from the Progenitor Cell Biology Consortium (PCBC) Synapse Portal. Independent validation sets with large sample size and common clinic pathological characteristics were obtained from the Gene Expression Omnibus (GEO) database. we constructed a KIRC-specific stemness prediction model using an algorithm called one-class logistic regression based on the expression and alternative splicing data to predict stemness indices of KIRC patients, and the model was externally validated. We identify stemness-associated alternative splicing events (SASEs) by analyzing different alternative splicing event between high- and low- stemness groups. Univariate Cox and multivariable logistic regression analysisw as carried out to detect the prognosis-related SASEs respectively. The area under curve (AUC) of receiver operating characteristic (ROC) was performed to evaluate the predictive values of our model.ResultsHere, we constructed a KIRC-specific stemness prediction model with an AUC of 0.968,and to provide a user-friendly interface of our model for KIRC stemness analysis, we have developed KIRC Stemness Calculator and Visualization (KSCV), hosted on the Shiny server, can most easily be accessed via web browser and the url https://jiang-lab.shinyapps.io/kscv/ . When applied to 605 KIRC patients, our stemness indices had a higher correlation with the gender, smoking history and metastasis of the patients than the previous stemness indices, and revealed intratumor heterogeneity at the stemness level. We identified 77 novel SASEs by dividing patients into high- and low- stemness groups with significantly different outcome and they had significant correlations with expression of 17 experimentally validated splicing factors. Both univariate and multivariate survival analysis demonstrated that SASEs closely correlated with the overall survival of patients.ConclusionsBasing on the stemness indices, we found that not only immune infiltration but also alternative splicing events showed significant different at the stemness level. More importantly, we highlight the critical role of these differential alternative splicing events in poor prognosis, and we believe in the potential for their further translation into targets for immunotherapy.

Dataset Information

Celastrol Attenuates Lipid Accumulation and Stemness of Clear Cell Renal Cell Carcinoma via CAV-1/LOX-1 Pathway.

Publications

Celastrol Attenuates Lipid Accumulation and Stemness of Clear Cell Renal Cell Carcinoma via CAV-1/LOX-1 Pathway.

Similar Datasets

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