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High expression of PKA regulatory subunit 1A protein is related to proliferation of human melanoma cells

Oncogene volume 27, pages 1834–1843 (2008)Cite this article

Abstract

The cAMP–protein kinase A (PKA) pathway is the major signal transduction pathway involved in melanocyte-stimulating hormone receptor-mediated signaling and melanin production, whereas its role in the control of melanocyte proliferation is still controversial. In this study, we evaluated the effects of selective activation of the different PKA regulatory subunits type 1A (R1A) and type 2B (R2B) on melanocyte proliferation. Immunohistochemistry demonstrated that normal melanocytes lacked R1A protein whereas this subunit was highly expressed in all human melanomas studied (N=20) and in six human melanoma cell lines. Pharmacological activation of the R2 subunits by the cAMP analogue 8-Cl-cAMP inhibited proliferation and increased caspase-3 activity by 68.77±10.5 and 72±9% respectively, in all cell lines with the exception of the only p53-mutated one. Similar effects were obtained by activating R2 subunits with other analogues and by silencing R1A expression. The antiproliferative and proapoptotic effects of 8-Cl-cAMP were comparable to those observed with commonly used antitumoral drugs. Moreover, 8-Cl-cAMP potentiated the effects of these drugs on both cell proliferation and caspase-3 activity. In conclusion, this study first reports that human melanomas are characterized by a high R1/R2 ratio and that pharmacological and genetic manipulations able to revert this unbalanced expression cause significant antiproliferative and proapoptotic effects in melanoma cells.

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Acknowledgements

This work was supported by AIRC (Associazione Italiana Ricerca Cancro), Milan and by Ricerca Corrente Funds of Fondazione Policlinico IRCCS, Milan. PRIN grant 2006060982-002, Rome.

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Authors and Affiliations

  1. Department of Medical Sciences, Endocrine Unit, University of Milan, Fondazione Ospedale Maggiore IRCCS, Milan, Italy

    G Mantovani, S Bondioni, A G Lania, E Peverelli, P Beck-Peccoz & A Spada

  2. Unit of Melanoma Genetics, Istituto Nazionale per lo Studio e la Cura dei Tumori IRCCS, Milan, Italy

    M Rodolfo

  3. Department of Immunology and Inflammation, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy

    N Polentarutti & T Veliz Rodriguez

  4. Department of Medicine, Pathology Unit, Surgery and Dentistry, AO San Paolo and Fondazione Ospedale Maggiore IRCCS, Milan, Italy

    S Ferrero & S Bosari

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  1. G Mantovani
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  2. S Bondioni
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  3. A G Lania
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  4. M Rodolfo
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  10. P Beck-Peccoz
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  11. A Spada
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Correspondence to A Spada.

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Mantovani, G., Bondioni, S., Lania, A. et al. High expression of PKA regulatory subunit 1A protein is related to proliferation of human melanoma cells. Oncogene 27, 1834–1843 (2008). https://doi.org/10.1038/sj.onc.1210831

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  • DOI: https://doi.org/10.1038/sj.onc.1210831

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