Activation of GRP/GRP-R signaling contributes to castration-resistant prostate cancer progression

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.

Membrane metalloendopeptidase suppresses prostate carcinogenesis by attenuating effects of gastrin-releasing peptide on stem/progenitor cells

“…To further assess the relevance of our observations to human disease we tested the effects of GRP and [Tyr 4 , D-Phe 12 ]-Bombesin on PTEN-deficient androgen-refractory human prostate cancer cells DU145 and PC3. Consistent with previous reports 34,41,48 , GRP promoted cell proliferation, migration, and invasion, and these effects were negated by addition of [Tyr 4 , D-Phe 12 ]-Bombesin in both cell lines ( Supplementary Fig. 6).…”

“…While most prostate cancers are adenocarcinomas, a significant percentage also have dysregulation of neuroendocrine signaling, such as excessive accumulation of cells with neuroendocrine differentiation and/or overproduction of neuropeptides 8,19,27 . A large amount of data demonstrate neuropeptides, such as gastrin-releasing peptide (GRP), are associated with accelerated prostate cancer progression and inferior prognosis 34,45,48 . GRP can promote cell proliferation, and accelerate migration and invasion of prostate cancer cells 15,34,41,54 .…”

“…A large amount of data demonstrate neuropeptides, such as gastrin-releasing peptide (GRP), are associated with accelerated prostate cancer progression and inferior prognosis 34,45,48 . GRP can promote cell proliferation, and accelerate migration and invasion of prostate cancer cells 15,34,41,54 . Targeting of the GRP receptor suppresses growth in cell culture and xenograft models 26 .…”

Somatostatin receptor subtype 1 as a potential diagnostic marker and therapeutic target in prostate cancer

“…Also, IRS2 is a known oncogene related with insulin and IGF‐I function, and VIPR1 is overexpressed in several tumors, acting as receptor of vasoactive intestinal peptide (VIP), which shows anti‐apoptotic and pro‐angiogenic function . This might be an important observation since other growth factors, such as GHRH or gastrin‐releasing peptide, have also been described as PCa enhancer, being even used as therapeutic targets . Additionally, SLC45A3 has been shown to be usually present in malignant prostate tissue and LIFR has been previously reported as an unfavorable prognosis marker in melanoma, and to be associated with reduced drug response in breast cancer .…”

Membrane metalloendopeptidase suppresses prostate carcinogenesis by attenuating effects of gastrin-releasing peptide on stem/progenitor cells

“…While most prostate cancers are adenocarcinomas, a significant percentage also have dysregulation of neuroendocrine signaling, such as excessive accumulation of cells with neuroendocrine differentiation and/or overproduction of neuropeptides [2][3][4] . A large amount of data demonstrate neuropeptides, such as gastrin-releasing peptide (GRP), are associated with accelerated prostate cancer progression and inferior prognosis [5][6][7] . GRP can promote cell proliferation and accelerate migration and invasion of prostate cancer cells 5,[8][9][10] .…”