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Glucocorticoid receptor upregulation increases radioresistance and triggers androgen independence of prostate cancer
Author(s) -
Chen Xiaodong,
Chen Feng,
Ren Yu,
Weng Guobin,
Keng Peter C.,
Chen Yuhchyau,
Lee Soo Ok
Publication year - 2019
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.23861
Subject(s) - radioresistance , lncap , prostate cancer , androgen receptor , cancer research , glucocorticoid receptor , androgen , downregulation and upregulation , biology , medicine , endocrinology , glucocorticoid , radiation therapy , cancer , hormone , gene , biochemistry
Background Despite the overall success of radiotherapy, a significant number of patients develop radioresistance, which leads to local regional recurrence and distant metastasis. We studied whether repeated radiation treatment promotes androgen‐independent survival of prostate cancer (PCa) cells and their metastatic potential. We also studied whether glucocorticoid receptor (GR) increase in radioresistant cells is associated with acquisition of these aggressive characteristics. Methods Radioresistant LNCaP (LNCaPR18) and C4‐2 (C4‐2R26) PCa sublines were developed by repeated radiation treatments of parental cells. Levels and activations of androgen receptor (AR) and GR in radioresistant PCa cells and respective parental cells were investigated in quantitative real‐time polymerase chain reaction/Western blot analyses and immunofluorescence staining. Androgen‐independent survival of radioresistant cells was tested in in vitro cell growth assays and the castration‐resistant survival of these cell‐derived tumors were investigated in mouse xenografts. Results Higher GR levels, but lower AR levels were detected in radioresistant cells than in parental cells. Radiation‐induced GR upregulation was associated with increased intracellular cyclic adenosine monophosphate. As a consequence of GR activation, LNCaPR18 cells survived well in an androgen‐depleted culture condition while parental cells could not. Results of in vivo mouse studies showed survival of LNCaPR18 cell‐derived tumors in castrated mice while parental cell‐derived tumors regressed. The growth of LNCaPR18 cell‐derived tumors in castrated mice was impaired when treated with the anti‐GR agent mifepristone. In experiments with C4‐2/C4‐2R26 cell sets, GR activation in C4‐2R26 cells increased their metastatic potential. Conclusion GR activation in radioresistant cells mediates androgen independence and facilitates PCa progression.