TGF-ß causes Docetaxel resistance in Prostate Cancer via the induction of Bcl-2 by acetylated KLF5 and Protein Stabilization.
Theranostics
; 10(17): 7656-7670, 2020.
Article
in En
| MEDLINE
| ID: mdl-32685011
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-ß 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-ß-induced DTX resistance. Moreover, KLF5 acetylation at lysine 369 mediates DTX resistance in vitro and in vivo. We showed that the TGF-ß/acetylated KLF5 signaling axis activates Bcl-2 expression transcriptionally. Furthermore, DTX-induced Bcl-2 degradation depends on a proteasome pathway, and TGF-ß inhibits DTX-induced Bcl-2 ubiquitination.Conclusion:
Our study demonstrated that the TGF-ß-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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Prostatic Neoplasms
/
Drug Resistance, Neoplasm
/
Proto-Oncogene Proteins c-bcl-2
/
Kruppel-Like Transcription Factors
/
Transforming Growth Factor beta1
/
Docetaxel
Type of study:
Etiology_studies
/
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Theranostics
Year:
2020
Document type:
Article
Affiliation country:
United States
Publication country:
AU
/
AUSTRALIA
/
AUSTRÁLIA