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

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is known to play crucial roles in tumor radioresistance; however, the molecular mechanisms responsible for the promotion of tumor radioresistance by HIF-1 alpha remain unclear beta-catenin is known to be involved in the metastatic potential of prostate cancer (PCa). In this study, to investigate the role of HIF-1 alpha and beta-catenin in the radioresistance of PCa, two PCa cell lines, LNCaP and C4-2B, were grouped as follows: Negative control (no treatment), HIF-1 alpha overexpression group (transfected with HIF-1 alpha overexpression plasmid) and beta-catenin silenced group (transfected with HIF-1 alpha plasmids and beta-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-1 alpha overexpression plasmid led to an enhanced beta-catenin nuclear translocation, while beta-catenin silencing inhibited beta-catenin nuclear translocation. The enhanced beta-catenin nuclear translocation induced by HIF-1 alpha 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-1 alpha overexpression enhanced beta-catenin nuclear translocation, which led to the activation of the beta-catenin/NHEJ signaling pathway and increased cell proliferation, cell invasion and DNA repair. These results thus suggest that HIF-1 alpha overexpression promotes the radioresistance of PCa cells.