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

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.

• Authors: Yixiang Li, Baotong Zhang, Lingwei Xiang, Siyuan Xia, Omer Kucuk, Xingming Deng, Lawrence H Boise, Jin-Tang Dong
• Journal: Theranostics (Theranostics) Vol. 10 Issue 17 Pg. 7656-7670 ( 2020) ISSN: 1838-7640 [Electronic] Australia
• PMID: 32685011 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © The author(s).

Chemical References

• BCL2 protein, human
• KLF5 protein, human
• Kruppel-Like Transcription Factors
• Proto-Oncogene Proteins c-bcl-2
• Recombinant Proteins
• TGFB1 protein, human
• Transforming Growth Factor beta1
• Docetaxel
• Proteasome Endopeptidase Complex

Topics

• Acetylation
• Animals
• Apoptosis (genetics)
• Cell Line, Tumor
• Docetaxel (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Regulation, Neoplastic
• Gene Knockout Techniques
• HEK293 Cells
• Humans
• Kruppel-Like Transcription Factors (genetics, metabolism)
• Male
• Mice
• Prostatic Neoplasms (drug therapy, genetics, pathology)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Stability
• Proteolysis (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Recombinant Proteins (metabolism)
• Transcriptional Activation
• Transforming Growth Factor beta1 (metabolism)
• Ubiquitination (drug effects, genetics)
• Xenograft Model Antitumor Assays