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Growth hormone-releasing hormone antagonists abolish the transactivation of human epidermal growth factor receptors in advanced prostate cancer models

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Summary

Growth hormone-releasing hormone (GHRH) and its receptors have been implicated in a variety of cellular phenotypes related with tumorigenesis process. Human epidermal growth factor receptor family members (HER) such as EGFR and HER2 are involved in mitogenic signaling pathways implicated in the progression of prostate cancer. We analyzed the cross-talk between GHRH and EGF receptors in prostate cancer. The effects of GHRH in HER signaling were evaluated on human androgen-independent PC3 prostate cancer cells in vitro and GHRH antagonist in vitro and in nude mice xenografts of PC3 prostate cancer. Time-course studies indicated that GHRH had a stimulatory activity on both the expression of EGFR and HER2. GHRH analogues, JMR-132 and JV-1–38, endowed with antagonistic activity for GHRH receptors, abrogated the response to GHRH in PC3 cells. GHRH stimulated a rapid ligand-independent activation of EGFR and HER2 involving at least cAMP/PKA and Src family signaling pathways. GHRH also stimulated a slow ligand-dependent activation of EGFR and HER2 involving an extracellular pathway with an important role for ADAM. Preliminary results also revealed an increase of mRNA for GHRH and GHRH receptor induced by EGF. The inhibition of tumor growth, in vivo, was associated with a substantial reduction in the expression of mRNA and protein levels of EGFR and HER2 in the tumors. GHRH antagonist JV-1–38, significantly decreased the phosphorylated Src levels. The cross-talk between HER and GHRH-R may be impeded by combining drugs acting upon GHRH receptors and HER family members in human advanced prostate cancer.

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Acknowledgments

This work was supported by the Junta de Comunidades de Castilla-La Mancha [grant number PII10-0189-3222 to A.M.B.] and by the University of Alcalá [FPU/UAH grant to L.M.M.]. Synthesis of GHRH antagonists in the laboratory of AVS was supported by the Medical Research Service of the Veterans Affairs Department.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Systems Biology, Unit of Biochemistry and Molecular Biology, University of Alcalá, 28871, Alcalá de Henares, Spain

    Laura Muñoz-Moreno, M. José Carmena & Ana M. Bajo

  2. Department of Biomedicine and Biotechnology, Unit of Cell Biology, University of Alcalá, 28871, Alcalá de Henares, Spain

    M. Isabel Arenas

  3. Veterans Administration Medical Center and Departments of Pathology and Medicine, Division of Oncology and Hematology, University of Miami Miller School of Medicine and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL, 33125, USA

    Andrew V. Schally

  4. Department of Systems Biology, Unit of Biochemistry and Molecular Biology, Faculty of Medicine and Health Sciences, University of Alcalá, 28871, Alcalá de Henares, Spain

    Juan C. Prieto

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  1. Laura Muñoz-Moreno
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  2. M. Isabel Arenas
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  3. M. José Carmena
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  4. Andrew V. Schally
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  6. Ana M. Bajo
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Correspondence to Juan C. Prieto.

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Muñoz-Moreno, L., Arenas, M.I., Carmena, M.J. et al. Growth hormone-releasing hormone antagonists abolish the transactivation of human epidermal growth factor receptors in advanced prostate cancer models. Invest New Drugs 32, 871–882 (2014). https://doi.org/10.1007/s10637-014-0131-4

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  • DOI: https://doi.org/10.1007/s10637-014-0131-4

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