Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases

Abstract

The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy of current therapies. Novel therapeutic strategies for the treatment of CRPC are needed. Antagonists of hypothalamic growth hormone-releasing hormone (GHRH) inhibit growth of various malignancies, including androgen-dependent and independent prostate cancer, by suppressing diverse tumoral growth factors, especially GHRH itself, which acts as a potent autocrine/paracrine growth factor in many tumors. We evaluated the effects of the GHRH antagonist, JMR-132, on PC-3 human androgen-independent prostate cancer cells in vitro and in vivo. JMR-132 suppressed the proliferation of PC-3 cells in vitro in a dose-dependent manner and significantly inhibited growth of PC-3 tumors by 61% ( P < 0.05). The expression of GHRH, GHRH receptors, and their main splice variant, SV1, in PC-3 cells and tumor xenografts was demonstrated by RT-PCR and Western blot. The content of GHRH protein in PC-3 xenografts was lowered markedly, by 66.3% ( P < 0.01), after treatment with JMR-132. GHRH induced a significant increase in levels of ERK, but JMR-132 abolished this outcome. Our findings indicate that inhibition of PC-3 prostate cancer by JMR-132 involves inactivation of Akt and ERK. The inhibitory effect produced by GHRH antagonist can result in part from inactivation of the PI3K/Akt/mammalian target of rapamycin and Raf/MEK/ERK pathways and from the reduction in GHRH produced by cancer cells. Our findings support the role of GHRH as an autocrine growth factor in prostate cancer and suggest that antagonists of GHRH should be considered for further development as therapy for CRPC.

Novel GHRH antagonists suppress the growth of human malignant melanoma by restoring nuclear p27 function

“…It has been recently discovered that inhibition of tumor growth by GHRH antagonists involves inactivation of Akt. 6,38 Consequently, the GHRH antagonist may have induced p27 translocation indirectly by interfering with the PI3K/Akt/mTOR pathway. Impaired ability to undergo apoptosis is one of the main reasons for the resistance to therapy seen in most advanced melanoma cases.…”

“…17 Direct mechanisms involved in the dominant antitumor effects of GHRH antagonists appear to be based on blockage of the autocrine action of GHRH on tumors and on inhibition of the local production of IGF-I/II. 6,18 Our group has demonstrated the presence of the pituitary type GHRH-receptor (pGHRH-R) and 4 truncated splice variants (SVs) of the GHRH-R in human prostate and breast cancer specimens as well as different cancer cell lines. [19][20][21] SV1 has the greatest structural similarity to the pGHRH-R, differing only in a short segment of the extracellular ligand-binding domain.…”

“…5 In turn, GH stimulates the production of hepatic insulin-like growth factor I (IGF-I), which is a potent mitogen for many cancers. 6 Additionally, GHRH and GHRH-R are not confined to the hypothalamic-pituitary axis, but are also produced by various extrahypothalamic sites. 7 GHRH and GHRH-R modulate cell proliferation and apoptosis in many tissues.…”

Antagonists of growth hormone releasing hormone (GHRH) given before whole body radiation lead to modulation of radiation response and organ-specific changes in the expression of angiogenesis

“…The finding that GHRH can function as a tumor growth factor [5][6][7][8][9][12][13][14][15][16] increased interest in the development of GHRH antagonists. Antagonists of GHRH can exert both direct and indirect effects on tumors and other tissues.…”

“…All genes represented by the array showed a single peak on the melting curve characteristic of the specific products. Data analysis of gene expression was performed as described [16]. Briefly, using Excel based PCR Array Data Analysis software provided by manufacturer: fold-changes in gene expression were calculated using the ΔΔCt method and five stably expressed housekeeping genes (B2M, HPRT1, RPL13A, GAPDH, and ACTB) were used for normalization of the results.…”