[Activation of HIF-1α/ß-catenin signal pathway leads to radioresistance of prostate cancer cells].
Zhonghua Yi Xue Za Zhi
; 98(32): 2552-2558, 2018 Aug 28.
Article
in Zh
| MEDLINE
| ID: mdl-30220138
ABSTRACT
Objective:
To investigate the role of hypoxia-inducible factor-1α (HIF-1α) and ß-catenin in radioresistance of prostate cancer (PCa) cells.Method:
Two PCa cell lines, LNCaP and C4-2B, were grouped as negative control (no treatment), HIF-1α overexpression group (transfected with HIF-1α plasmids), and ß-catenin silencing group (transfected with HIF-1α plasmids and ß-catenin-shRNA). Cell proliferation, cycle, invasion, and radiosensitivity were measured under normal or hypoxic condition. Radiosensitivity was tested in two mice PCa models (the LNCaP orthotopic BALB/c-nu mice model and the C4-2B subcutaneous SCID mice model).Results:
In both LNCaP and C4-2B cells, HIF-1α transfection led to an enhanced ß-catenin nuclear translocation, while ß-catenin silencing inhibited the ß-catenin nuclear translocation. Enhanced ß-catenin nuclear translocation caused by HIF-1α overexpression resulted in enhanced cell proliferation and invasion, altered cell cycle distribution, reduced apoptosis, and improved non-homologous-end-joining (NHEJ) repair under irradiation condition. In vivo imaging of orthotopic models showed that HIF-1α overexpression LNCaP cells produced tumors with 3-fold volume (P=0.003 1) and 2-fold wet weight (P=0.039 4) than those by negative control cells at day 21, and ß-catenin silencing cells aberrantly reduced both tumor volume (P=0.000 3) and wet weight (P=0.017 5) than HIF-1α overexpression cells. In addition, C4-2B subcutaneous models showed similar tumor promotion effects induced by HIF-1α overexpression (tumor volume P=0.000 1 and wet weight P=0.047 3) and suppressive effects by ß-catenin silencing (tumor volume P<0.000 1 and wet weight P=0.022 1) as LNCaP orthotopic xenograft with regard to tumor volume and wet weight.Conclusions:
HIF-1α overexpression enhanced ß-catenin nuclear translocation, which led to the activation of the ß-catenin/NHEJ signaling pathway and increased cell proliferation, invasion, and DNA repair. These results suggest that HIF-1α overexpression led to radioresistance of PCa cells.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Signal Transduction
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
Zh
Journal:
Zhonghua Yi Xue Za Zhi
Year:
2018
Document type:
Article
Affiliation country:
China
Publication country:
CHINA
/
CN
/
REPUBLIC OF CHINA