β-catenin nuclear translocation induced by HIF-1a overexpression leads to the radioresistance of prostate cancer

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

YONG,Li,MINGCHUAN,Zuo,XUEMEI,BASOURAKOS,SPYRIDON P.,Zhang,JIAO,Zhao,JIAHUI,Han,Yili,Lin,YUNHUA,Wang Luo (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Hypoxia-inducible factor-1a (HIF-1a) is known to play crucial roles in tumor radioresistance; however, the molecular mechanisms responsible for the promotion of tumor radioresistance by HIF-1a remain unclear. β-catenin is known to be involved in the metastatic potential of prostate cancer (PCa). In this study, to investigate the role of HIF-1a and β-catenin in the radioresistance of PCa, two PCa cell lines, LNCaP and C4-2B, were grouped as follows: Negative control (no treatment), HIF-1a overexpression group (transfected with HIF-1a overexpression plasmid) and β-catenin silenced group (transfected with HIF-1a plasmids and β-catenin-shRNA). Cell proliferation, cell cycle, cell invasion and radiosensitivity were examined under normal or hypoxic conditions. In addition, radiosensitivity was examined in two mouse PCa models (the LNCaP orthotopic BALB/c-nu mice model and the C4-2B subcutaneous SCID mice model). Our results revealed that in both the LNCaP and C4-2B cells, transfection with HIF-1a overexpression plasmid led to an enhanced β-catenin nuclear translocation, while β-catenin silencing inhibited β-catenin nuclear translocation. The enhanced β-catenin nuclear translocation induced by HIF-1a overexpression resulted in an enhanced cell proliferation and cell invasion, an altered cell cycle distribution, decreased apoptosis, and improved non-homologous end joining (NHEJ) repair under normal and irradiation conditions. Similar results were observed in the animal models. HIF-1a overexpression enhanced β-catenin nuclear translocation, which led to the activation of the β-catenin/NHEJ signaling pathway and increased cell proliferation, cell invasion and DNA repair. These results thus suggest that HIF-1a overexpression promotes the radioresistance of PCa cells.

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Language: English

Date: 2018

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