Glucocorticoid receptor upregulation increases radioresistance and triggers androgen independence of prostate cancer

Abstract

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.

Synergistic Radiosensitization by Gold Nanoparticles and the Histone Deacetylase Inhibitor SAHA in 2D and 3D Cancer Cell Cultures

“…These drawbacks encompass inherent or acquired radioresistance which is frequently observed in certain breast, non-small cell lung and androgen-independent prostate cancers. To overcome such radioresistance an increased irradiation dose should be applied, ultimately leading to the undesired consequences of damaging healthy organs and tissues in the anatomical proximity of the targeted tumor [63][64][65][66][67][68]. Therefore, in recent years great impetus has been gained in developing and optimizing various types of materials for radiation-enhancing purposes in order to avoid the employment of excessisve radiation doses to eradicate cancer and simultaniously to protect healthy tissues.…”

Upregulation of glucocorticoid receptor‐mediated glucose transporter 4 in enzalutamide‐resistant prostate cancer

“…Although several mechanisms of Enz resistance, including AR mutations, the induction of AR splice variants, and AR‐related gene upregulation, have been reported, 2‐5 the proposed mechanisms cannot fully explain Enz resistance. In recent reports, GR upregulation has been identified as a driver of Enz resistance 6‐8 . Activation of AR signals by GR binding to the AR gene, 8,9 or activation of an AR‐independent pathway by GR, could contribute to Enz‐resistance 6,8 ; however, the detailed mechanism of how GR‐regulated pathways contribute to Enz resistance has not yet been clarified.…”

Human Papillomavirus Infection in Head and Neck Squamous Cell Carcinomas: Transcriptional Triggers and Changed Disease Patterns

“…Glucocorticoid hormone exerts regulatory action on HPV16 gene expression during growth and differentiation of cervical cancer (Khare et al, 1997). In prostate cancer GR increases radioresistance and triggers androgen hormone independence (Chen et al, 2019). However, there is no study so far on GR in relation to HNSCC.…”