Abstract
Introduction Radiotherapy is the mainstay in the treatment of prostate cancer. However, significant radioresistance of castration-resistant prostate cancer (CRPC) cells constitutes a main obstacle in the treatment of this disease. By using bioinformatic data mining methods, LOXL2 was found to be upregulated in both androgen-independent prostate cancer cell lines and radioresistant tumor samples collected from patients with prostate cancer. We speculate that LOXL2 may play an important role in the radioresistance of CRPC cells. Methods The effect of LOXL2 knockdown on the radiosensitivity of androgen-independent prostate cancer cells lines was measured by the clonogenic assay and xenograft tumor experiments under in vitro and in vivo conditions, respectively. In studies on the mechanism, we focused on the EMT phenotype changes and cell apoptosis changes induced by LOXL2 knockdown in DU145 cells. The protein levels of three EMT biomarkers, namely, E-cadherin, vimentin, and N-cadherin, were measured by western blotting and immunohistochemical staining. Cell apoptosis after irradiation was measured by flow cytometry and caspase-3 activity assay. Salvage experiment was also conducted to confirm the possible role of EMT in the radiosensitization effect of LOXL2 knockdown in CRPC cells. Results LOXL2 knockdown in CRPC cells enhanced cellular radiosensitivity under both in vitro and in vivo conditions. A significant reversal of EMT was observed in LOXL2-silenced DU145 cells. Cell apoptosis after irradiation was significantly enhanced by LOXL2 knockdown in DU145 cells. Results from the salvage experiment confirmed the key role of EMT process reversal in the radiosensitization effect of LOXL2 knockdown in DU145 cells. Conclusions LOXL2 plays an important role in the development of cellular radioresistance in CRPC cells. Targeting LOXL2 may be a rational avenue to overcome radioresistance in CRPC cells. A LOXL2-targeting strategy for CRPC treatment warrants detailed investigation in the future.
Highlights
Radiotherapy is the mainstay in the treatment of prostate cancer
A pool of 189 differentially expressed genes (DEGs) was identified in castrationresistant prostate cancer (CRPC) cell lines as compared with androgendependent cell lines
Within the intersection DEGs of the two datasets, we observed that lysyl oxidase-like 2 (LOXL2) was consistently upregulated in CRPC cell lines, as determined in the GEO dataset, and radioresistant prostate cancer samples, as determined in the TCGA dataset
Summary
Radiotherapy is the mainstay in the treatment of prostate cancer. significant radioresistance of castrationresistant prostate cancer (CRPC) cells constitutes a main obstacle in the treatment of this disease. We speculate that LOXL2 may play an important role in the radioresistance of CRPC cells. The effect of LOXL2 knockdown on the radiosensitivity of androgen-independent prostate cancer cells lines was measured by the clonogenic assay and xenograft tumor experiments under in vitro and in vivo conditions, respectively. Salvage experiment was conducted to confirm the possible role of EMT in the radiosensitization effect of LOXL2 knockdown in CRPC cells. LOXL2 knockdown in CRPC cells enhanced cellular radiosensitivity under both in vitro and in vivo conditions. Results from the salvage experiment confirmed the key role of EMT process reversal in the radiosensitization effect of LOXL2 knockdown in DU145 cells. LOXL2 plays an important role in the development of cellular radioresistance in CRPC cells. Its expression profile and biochemical role in castration evolution as well as the radiosensitivity of prostate cancer cells were largely unknown
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