GHRH agonist MR409 inhibits human xenograft cancers in vivo by down-regulating GHRH receptors
Background
While growth hormone-releasing hormone (GHRH) antagonists have shown promise in inhibiting various human cancer cell lines and experimental tumors, the role of GHRH agonists in oncology has been less clear, with some in vitro studies suggesting pro-proliferative effects. GHRH and its receptors are widely expressed in many human tumors, implicating the GHRH pathway in carcinogenesis. This study investigates the paradoxical in vivo anti-tumor effects of a GHRH agonist, aiming to elucidate its mechanism, particularly concerning GHRH receptor modulation, and explore its potential as a novel therapeutic strategy.
Study Design
Researchers investigated the GHRH agonist MR409 on human cancer cells in vitro and in vivo. For in vitro studies, H446 (small cell lung cancer), HCC827, and H460 (non-small cell lung cancer) cells were treated with MR409 to assess viability, apoptosis, cAMP production, and protein expression via Western blot. For in vivo experiments, nude mice were xenografted with HCC827, H460, or H446 lung cancers, as well as gastric, pancreatic, urothelial, prostatic, mammary, and colorectal cancers. Mice received MR409 at 5 μg/day s.c. for 4 to 8 weeks, with tumor growth inhibition and GHRH receptor expression in tumors and pituitary as primary endpoints.
Results
In vitro, MR409 promoted cell viability, reduced cell apoptosis, and induced cAMP production in lung cancer cells. Western blot analysis showed MR409 up-regulated cyclins D1 and D2, cyclin-dependent kinases 4 and 6, and significantly increased expression of the pituitary-type GHRH receptor (pGHRH-R) and its splice-variant (SV1), while down-regulating p27kip1. However, these in vitro agonistic effects contrasted sharply with in vivo findings. > MR409 significantly suppressed growth of HCC827, H460, and H446 xenograft tumors by 48.2%, 48.7%, and 65.6%, respectively, in nude mice. This tumor inhibition by MR409 was consistently accompanied by the down-regulation of pGHRH-R and SV1 expression in both the pituitary gland and the tumors themselves. Similar tumor inhibitory effects were observed across various other human cancer xenografts, including gastric, pancreatic, urothelial, prostatic, mammary, and colorectal cancers.
Key Findings
- MR409 promoted human lung cancer cell viability and reduced apoptosis in vitro.
- MR409 up-regulated cyclins D1/D2, CDK4/6, and pGHRH-R/SV1 expression in vitro.
- MR409 inhibited HCC827 xenograft growth by 48.2% in nude mice.
- MR409 inhibited H460 xenograft growth by 48.7% and H446 by 65.6% in nude mice.
- Tumor inhibition by MR409 was accompanied by down-regulation of pGHRH-R and SV1 in vivo.
Why It Matters
This study reveals a critical, counterintuitive mechanism: GHRH agonists can exert potent anti-tumor effects in vivo by down-regulating GHRH receptors, despite initial pro-proliferative signals in vitro. This parallels the established mechanism of LHRH agonists in sex hormone-dependent cancers, suggesting a broader principle of receptor desensitization for therapeutic benefit. For peptide users and clinicians, this opens a novel avenue for oncological intervention with GHRH agonists, potentially expanding treatment options beyond GHRH antagonists. While preclinical, the consistent efficacy across multiple cancer types and the clear mechanistic link to receptor down-regulation make this a compelling area for further clinical translation, though specific human protocols are far from established.
ghrh-agonist
mr409
cancer
lung-cancer
xenograft
preclinical-animal