TGF-beta causes Docetaxel resistance in Prostate Cancer via the induction of Bcl-2 by acetylated KLF5 and Protein Stabilization

• Type of Material: Article
• Authors: Yixiang Li, Emory University; Baotong Zhang, Emory University; Lingwei Xiang, ICF; Siyuan Xia, Emory University; Omer Kucuk, Emory University; Xingming Deng, Emory University; Lawrence Boise, Emory University; Jin-Tang Dong, Emory University
• Language: English
• Date: 2020-01-01
• Publisher: Ivyspring International Publishing
• Publication Version: Final Published Version
• Copyright Statement: © 2020 Ivyspring International Publisher.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.7150/thno.44567
• Title of Journal or Parent Work: Theranostics
• Volume: 10
• Issue: 17
• Start Page: 7656
• End Page: 7670
• Grant/Funding Information: The research reported in this publication was supported in part by the Integrated Cellular Imaging Core Facility and Winship Research Pathology Core Lab of Emory University under NIH/NCI award number P30CA138292.; This work was supported by grant W81XWH-18-1-0526 from the Department of Defense.
• Keywords: Stem-cells; Science & Technology; Up-regulation; Research & Experimental Medicine; Chemotherapy; Apoptosis; Epithelial-mesenchymal transition; Expression; Phosphorylation; Medicine, Research & Experimental; Mitoxantrone; KLF5 acetylation; Drug resistance; Transcription; Life Sciences & Biomedicine; prostate cancer; TGF-beta; docetaxel resistance; Bcl-2 degradation
• Research Categories: Health Sciences, Oncology; Health Sciences, Radiology; Biology, Cell

Abstract

Prostate cancer is the second leading cause of cancer-related death in the United States. As a first line treatment for hormone-refractory prostate cancer, docetaxel (DTX) treatment leads to suboptimal effect since almost all patients eventually develop DTX resistance. In this study, we investigated whether and how TGF-β affects DTX resistance of prostate cancer. Methods: Cytotoxicity of DTX in DU 145 and PC-3 cells was measured by CCK-8 and Matrigel colony formation assays. Resistance to DTX in DU 145 cells was examined in a xenograft tumorigenesis model. A luciferase reporter system was used to determine transcriptional activities. Gene expression was analyzed by RT-qPCR and Western blotting. Results: We found that KLF5 is indispensable in TGF-β-induced DTX resistance. Moreover, KLF5 acetylation at lysine 369 mediates DTX resistance in vitro and in vivo. We showed that the TGF-β/acetylated KLF5 signaling axis activates Bcl-2 expression transcriptionally. Furthermore, DTX-induced Bcl-2 degradation depends on a proteasome pathway, and TGF-β inhibits DTX-induced Bcl-2 ubiquitination. Conclusion: Our study demonstrated that the TGF-β-acetylated KLF5-Bcl-2 signaling axis mediates DTX resistance in prostate cancer and blockade of this pathway could provide clinical insights into chemoresistance of prostate cancer.