PUBLICATION
Activation of PKG restricts melanoma growth and invasion by interfering with the EGF/EGFR pathway
- Authors
- Quadri, M., Comitato, A., Palazzo, E., Tiso, N., Rentsch, A., Pellacani, G., Marconi, A., Marigo, V.
- ID
- ZDB-PUB-210716-14
- Date
- 2021
- Source
- The Journal of investigative dermatology 142(1): 201-211 (Journal)
- Registered Authors
- Tiso, Natascia
- Keywords
- EGFR pathway, Melanoma, PKG, Spheroids, Zebrafish, cGMP analogue
- MeSH Terms
-
- Animals
- Antineoplastic Agents/pharmacology*
- Cell Death/drug effects
- Cell Line, Tumor
- Cyclic GMP/analogs & derivatives
- Cyclic GMP/pharmacology*
- Cyclic GMP-Dependent Protein Kinases/metabolism*
- Drug Resistance, Neoplasm
- Epidermal Growth Factor/metabolism
- ErbB Receptors/metabolism
- Humans
- Melanocytes/physiology*
- Melanoma/metabolism*
- Neoplasm Invasiveness
- Neoplasm Metastasis
- Phosphorylation
- Proto-Oncogene Proteins c-akt/metabolism*
- Signal Transduction
- Skin Neoplasms/metabolism*
- Zebrafish
- PubMed
- 34265328 Full text @ J. Invest. Dermatol.
Citation
Quadri, M., Comitato, A., Palazzo, E., Tiso, N., Rentsch, A., Pellacani, G., Marconi, A., Marigo, V. (2021) Activation of PKG restricts melanoma growth and invasion by interfering with the EGF/EGFR pathway. The Journal of investigative dermatology. 142(1):201-211.
Abstract
Drug resistance mechanisms still characterize metastatic melanoma, despite new treatments have been recently developed. Targeting of the cGMP/protein kinase G (PKG) pathway is emerging as a therapeutic approach in cancer research. In this study, we evaluated the anticancer effects of two polymeric linked dimeric (PDL) cGMP analogues able to bind and activate PKG, called PKG-activator (PA) 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 analogue. We defined that, by triggering PKG, PA5 interfered with the EGF pathway as shown by lower EGFR phosphorylation and reduction of activated, phosphorylated forms of AKT and ERK1/2 in melanoma cells. Finally, PA5 significantly reduced the metastatic process in zebrafish. These studies open future perspectives for the cGMP analogue PA5 as a potential therapeutic strategy for melanoma.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping