It is believed that growth of
castration resistant
prostate cancer (CRPC) cells is enabled by sensitization to minimal residual post-castrate
androgen due to overexpression of the
androgen receptor (AR). Evidence is derived from
androgen-induced colony formation in the absence of cell-secreted factors or from studies involving forced AR overexpression in
hormone-dependent cells. On the other hand, standard cell line models established from CRPC patient
tumors (e.g., LNCaP and VCaP) are
hormone-dependent and require selection pressure in castrated mice to re-emerge as CRPC cells and the resulting
tumors then tend to be insensitive to the
androgen antagonist enzalutamide. Therefore, we examined established CRPC model cells produced by
castration of mice bearing
hormone-dependent cell line xenografts including CRPC cells overexpressing full-length AR (C4-2) or co-expressing wtAR and splice-variant AR-V7 that is incapable of
ligand binding (22Rv1). In standard colony formation assays, C4-2 cells were shown to be
androgen-dependent and sensitive to
enzalutamide whereas 22Rv1 cells were incapable of colony formation under identical conditions. However, both C4-2 and 22Rv1 cells formed colonies in
conditioned media derived from the same cells or from HEK293 fibroblasts that were proven to lack androgenic activity. This effect was (i) not enhanced by
androgen, (ii) insensitive to
enzalutamide, (iii) dependent on AR (in C4-2) and on AR-V7 and wtAR (in 22Rv1) and (iv) sensitive to inhibitors of several signaling pathways, similar to
androgen-stimulation. Therefore, during progression to CRPC in vivo, coordinate cellular changes accompanying overexpression of AR may enable cooperation between
hormone-independent activity of AR and actions of cellular secretory factors to completely override
androgen-dependence and sensitivity to drugs targeting hormonal factors.