Drug resistance mechanisms still characterize metastatic melanoma, despite the new treatments that have been recently developed. Targeting of the cGMP/protein kinase G pathway is emerging as a therapeutic approach in cancer research. In this study, we evaluated the anticancer effects of two polymeric-linked dimeric cGMP analogs able to bind and activate protein kinase G, called protein kinase G activators (PAs) 4 and 5. PA5 was identified as the most effective compound on melanoma cell lines as well as on patient-derived metastatic melanoma cells cultured as three-dimensional spheroids and in a zebrafish melanoma model. PA5 was able to significantly reduce cell viability, size, and invasion of melanoma spheroids. Importantly, PA5 showed a tumor-specific outcome because no toxic effect was observed in healthy melanocytes exposed to the cGMP analog. We defined that by triggering protein kinase G, PA5 interfered with the EGF pathway as shown by lower EGFR phosphorylation and reduction of activated, phosphorylated forms of protein kinase B and extracellular signal‒regulated kinase 1/2 in melanoma cells. Finally, PA5 significantly reduced the metastatic process in zebrafish. These studies open future perspectives for the cGMP analog PA5 as a potential therapeutic strategy for melanoma.

Activation of cGMP-Dependent Protein Kinase Restricts Melanoma Growth and Invasion by Interfering with the EGF/EGFR Pathway / Quadri, M.; Comitato, A.; Palazzo, E.; Tiso, N.; Rentsch, A.; Pellacani, G.; Marconi, A.; Marigo, V.. - In: JOURNAL OF INVESTIGATIVE DERMATOLOGY. - ISSN 0022-202X. - 142:(2022), pp. 201-211. [10.1016/j.jid.2021.06.011]

Activation of cGMP-Dependent Protein Kinase Restricts Melanoma Growth and Invasion by Interfering with the EGF/EGFR Pathway

Quadri M.
Methodology
;
Comitato A.
Membro del Collaboration Group
;
Palazzo E.
Methodology
;
Marconi A.
Supervision
;
Marigo V.
Conceptualization
2022

Abstract

Drug resistance mechanisms still characterize metastatic melanoma, despite the new treatments that have been recently developed. Targeting of the cGMP/protein kinase G pathway is emerging as a therapeutic approach in cancer research. In this study, we evaluated the anticancer effects of two polymeric-linked dimeric cGMP analogs able to bind and activate protein kinase G, called protein kinase G activators (PAs) 4 and 5. PA5 was identified as the most effective compound on melanoma cell lines as well as on patient-derived metastatic melanoma cells cultured as three-dimensional spheroids and in a zebrafish melanoma model. PA5 was able to significantly reduce cell viability, size, and invasion of melanoma spheroids. Importantly, PA5 showed a tumor-specific outcome because no toxic effect was observed in healthy melanocytes exposed to the cGMP analog. We defined that by triggering protein kinase G, PA5 interfered with the EGF pathway as shown by lower EGFR phosphorylation and reduction of activated, phosphorylated forms of protein kinase B and extracellular signal‒regulated kinase 1/2 in melanoma cells. Finally, PA5 significantly reduced the metastatic process in zebrafish. These studies open future perspectives for the cGMP analog PA5 as a potential therapeutic strategy for melanoma.
2021
142
201
211
Activation of cGMP-Dependent Protein Kinase Restricts Melanoma Growth and Invasion by Interfering with the EGF/EGFR Pathway / Quadri, M.; Comitato, A.; Palazzo, E.; Tiso, N.; Rentsch, A.; Pellacani, G.; Marconi, A.; Marigo, V.. - In: JOURNAL OF INVESTIGATIVE DERMATOLOGY. - ISSN 0022-202X. - 142:(2022), pp. 201-211. [10.1016/j.jid.2021.06.011]
Quadri, M.; Comitato, A.; Palazzo, E.; Tiso, N.; Rentsch, A.; Pellacani, G.; Marconi, A.; Marigo, V.
File in questo prodotto:
File Dimensione Formato  
1-s2.0-S0022202X21014202-main.pdf

accesso aperto

Tipologia: Versione dell'editore (versione pubblicata)
Dimensione 3.35 MB
Formato Adobe PDF
3.35 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1251711
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 8
  • ???jsp.display-item.citation.isi??? 8
social impact