Pd51-10 Estrogen Receptor Signals Promote Autophagy and M2 Macrophage Polarization in the Tki-Resistant RCC

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology II (PD51)1 May 2024PD51-10 ESTROGEN RECEPTOR SIGNALS PROMOTE AUTOPHAGY AND M2 MACROPHAGE POLARIZATION IN THE TKI-RESISTANT RCC Shuyuan Yeh, Huiyang Xu, Yixi Hu, Guosheng Yang, Jean Joseph, and Edward M. Messing Shuyuan YehShuyuan Yeh , Huiyang XuHuiyang Xu , Yixi HuYixi Hu , Guosheng YangGuosheng Yang , Jean JosephJean Joseph , and Edward M. MessingEdward M. Messing View All Author Informationhttps://doi.org/10.1097/01.JU.0001009360.84490.42.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Early studies indicated that estrogen receptor β (ERβ) could influence the progression of clear cell renal cell carcinoma (ccRCC). Its potential functions on regulating macrophages within the tumor microenvironment and the impacts on the sensitivity of tyrosine kinase inhibitor (TKI) treatment remain to be further studied. METHODS: The human cell lines: 786-O, A498, THP-1 and mouse RAW 264.7 cells were used. Lentiviral plasmids were used to generate gene engineering viral particles. The qPCR and Western blot were applied to evaluate the gene expressions at RNA and protein levels, respectively. The trans-well co-cultures of RCC cells with human macrophages with high vs. low ER expression were used to determine the changes of TKI sensitivity of RCC cells. Protein-DNA binding complexes were detected by Chromatin immunoprecipitation (ChIP) assays. The human non-coding RNA promoter was cloned into pGL3 vector for Luciferase assays. Preclinical mouse RCC model was used to evaluate the anti-cancer effect of TKI plus non-coding RNA blockage in TKI-resistant RCC. RESULTS: Autophagy may serve to mitigate the limited availability of external nutrients and sustain tumor cell viability. Our results from multiple cell line studies revealed that infiltrating macrophages could increase the ERβ/Egr1-mediated autophagy to decrease the TKI treatment sensitivity of RCC cells. Furthermore, the increased ERβ in RCC cells could function via a positive feedback mechanism to induce M2 macrophage polarization with increasing ARG1 to further decrease the TKI (sunitinib or pazopanib) sensitivity of ccRCC. The up-regulated ERβ could then transcriptionally increase the miRNA expression to decrease PTEN expression in macrophages in the tumor microenvironment. Detailed mechanism studies reveal the involvement of altering no-coding RNA function to control pTEN/p-AKT signaling. CONCLUSIONS: Here we found that ERβ might function via increasing the autophagy and M2 macrophage polarization to decrease the RCC cell sensitivity to the TKI treatment. Preclinical studies using in vivo mouse models also prove that targeting this newly identified ARG1/ERβ/p-AKT signaling by blocking the non-coding RNA and/or anti-estrogen leads to increase the TKI sensitivity to better suppress RCC progression, which, if successful in future clinical trial, may help in the development of a novel therapy to better suppress the ccRCC progression. Source of Funding: The study was partially supported by the URMC Urology Research fund © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e1069 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Shuyuan Yeh More articles by this author Huiyang Xu More articles by this author Yixi Hu More articles by this author Guosheng Yang More articles by this author Jean Joseph More articles by this author Edward M. Messing More articles by this author Expand All Advertisement PDF downloadLoading ...