Abstract
Prostate cancer is the second most frequent cancer diagnosed in men worldwide. Localized disease can be successfully treated, but advanced cases are more problematic. After initial effectiveness of androgen deprivation therapy, resistance quickly occurs. Therefore, we aimed to investigate the role of Hedgehog-GLI (HH-GLI) signaling in sustaining androgen-independent growth of prostate cancer cells. We found various modes of HH-GLI signaling activation in prostate cancer cells depending on androgen availability. When androgen was not deprived, we found evidence of non-canonical SMO signaling through the SRC kinase. After short-term androgen deprivation canonical HH-GLI signaling was activated, but we found little evidence of canonical HH-GLI signaling activity in androgen-independent prostate cancer cells. We show that in androgen-independent cells the pathway ligand, SHH-N, non-canonically binds to the androgen receptor through its cholesterol modification. Inhibition of this interaction leads to androgen receptor signaling downregulation. This implies that SHH-N activates the androgen receptor and sustains androgen-independence. Targeting this interaction might prove to be a valuable strategy for advanced prostate cancer treatment. Also, other non-canonical aspects of this signaling pathway should be investigated in more detail and considered when developing potential therapies.
Highlights
Prostate cancer is the second most frequent cancer diagnosed in men worldwide
GLI3 protein processing was inhibited after addition of DHT, which supports the finding of Li et al that in the presence of androgen androgen receptor (AR) binds GLI3 and inhibits its processing into the repressor f orm[20]
In LNCaP-AI cells prostate-specific antigen (PSA) and KLK2 expression was lower compared with LNCaP cells but elevated in comparison with their levels after short-term androgen deprivation, suggesting that AR activity was partly restored by alternative mechanisms to sustain androgen-independent growth (Fig. 1C)
Summary
Prostate cancer is the second most frequent cancer diagnosed in men worldwide. Localized disease can be successfully treated, but advanced cases are more problematic. We show that in androgen-independent cells the pathway ligand, SHH-N, non-canonically binds to the androgen receptor through its cholesterol modification Inhibition of this interaction leads to androgen receptor signaling downregulation. This implies that SHH-N activates the androgen receptor and sustains androgen-independence Targeting this interaction might prove to be a valuable strategy for advanced prostate cancer treatment. Since androgen receptor (AR) signaling is the main pathway ensuring prostate cancer cell growth, androgen deprivation therapy (ADT) has been the standard treatment option for patients with advanced forms of prostate cancer. Even though this therapy is effective initially, most patients progress to a poor-prognosis stage called castration-resistant prostate cancer (CRPC). This interaction is proposed to lead to activation of both AR and HH-GLI pathways, and subsequently to cell p roliferation[19,20]
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