Abstract
Numerous studies indicate that androgen receptor splice variants (ARVs) play a critical role in the development of castration-resistant prostate cancer (CRPC), including the resistance to the new generation of inhibitors of androgen receptor (AR) action. Previously, we demonstrated that activation of NF-κB signaling increases ARVs expression in prostate cancer (PC) cells, thereby promoting progression to CRPC. However, it is unclear how NF-κB signaling is activated in CRPC. In this study, we report that long-term treatment with anti-androgens increases a neuroendocrine (NE) hormone — gastrin-releasing peptide (GRP) and its receptor (GRP-R) expression in PC cells. In addition, activation of GRP/GRP-R signaling increases ARVs expression through activating NF-κB signaling. This results in an androgen-dependent tumor progressing to a castrate resistant tumor. The knock-down of AR-V7 restores sensitivity to antiandrogens of PC cells over-expressing the GRP/GRP-R signaling pathway. These findings strongly indicate that the axis of Androgen-Deprivation Therapy (ADT) induces GRP/GRP-R activity, activation NF-κB and increased levels of AR-V7 expression resulting in progression to CRPC. Both prostate adenocarcinoma and small cell NE prostate cancer express GRP-R. Since the GRP-R is clinically targetable by analogue-based approach, this provides a novel therapeutic approach to treat advanced CRPC.
Highlights
Numerous studies indicate that androgen receptor splice variants (ARVs) play a critical role in the development of castration-resistant prostate cancer (CRPC), including the resistance to the new generation of inhibitors of androgen receptor (AR) action [1,2,3,4,5]
The knock-down of AR-V7 restores sensitivity to antiandrogens of PC cells over-expressing the gastrin-releasing peptide (GRP)/GRP-R signaling pathway. These findings strongly indicate that the axis of Androgen-Deprivation Therapy (ADT) induces GRP/GRP-R activity, activation NF-κB and increased levels of AR-V7 expression resulting in progression to CRPC
Constitutive expression of GRP/GRP-R signaling is sufficient to increase ARVs expression through activation of NF-κB signaling resulting in castration-resistant growth of the previously androgen-dependent PC. These findings strongly indicate that the axis of ADT induces GRP/GRP-R activity which activates NF-κB that increases the expression of AR-V7, thereby causing the tumor to progress to CRPC
Summary
Numerous studies indicate that androgen receptor splice variants (ARVs) play a critical role in the development of castration-resistant prostate cancer (CRPC), including the resistance to the new generation of inhibitors of androgen receptor (AR) action [1,2,3,4,5]. The ARVs result in constitutive activation of the AR pathway thereby promoting prostate cancer (PC) cell growth at low concentrations of androgens [4, 6], enhance growth of androgen dependent xenografts in castrated mice [3] and the development of enzalutamide resistant PC [7]. Based on these findings, it has been proposed that ARVs can function as important drivers of CRPC [1,2,3, 5]. How NF-κB signaling is activated in response to Androgen-Deprivation Therapy (ADT) in PC patients is still not fully understood
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