Nitric oxide (NO) production in the tumor microenvironment is a common element in cancer. S-nitrosylation, the post-translational modification of cysteines by NO, is emerging as a key transduction mechanism sus-taining tumorigenesis. However, most oncoproteins that are regulated by S-nitrosylation are still unknown. Here we show that S-nitrosoglutathione reductase (GSNOR), the enzyme that deactivates S-nitrosylation, is hypo-expressed in several human malignancies. Using multiple tumor models, we demonstrate that GSNOR deficiency induces S-nitrosylation of focal adhesion kinase 1 (FAK1) at C658. This event enhances FAK1 autophosphorylation and sustains tumorigenicity by providing cancer cells with the ability to survive in suspension (evade anoikis). In line with these results, GSNOR-deficient tumor models are highly suscep-tible to treatment with FAK1 inhibitors. Altogether, our findings advance our understanding of the oncogenic role of S-nitrosylation, define GSNOR as a tumor suppressor, and point to GSNOR hypo-expression as a ther-apeutically exploitable vulnerability in cancer.
Rizza, S., Di Leo, L., Pecorari, C., Giglio, P., Faienza, F., Montagna, C., et al. (2023). GSNOR deficiency promotes tumor growth via FAK1 S-nitrosylation. CELL REPORTS, 42(1), 111997 [10.1016/j.celrep.2023.111997].
GSNOR deficiency promotes tumor growth via FAK1 S-nitrosylation
Rizza, Salvatore;Di Leo, Luca;Giglio, Paola;Faienza, Fiorella;Montagna, Costanza;Lin, Lin;De Zio, Daniela;Filomeni, Giuseppe
2023-01-31
Abstract
Nitric oxide (NO) production in the tumor microenvironment is a common element in cancer. S-nitrosylation, the post-translational modification of cysteines by NO, is emerging as a key transduction mechanism sus-taining tumorigenesis. However, most oncoproteins that are regulated by S-nitrosylation are still unknown. Here we show that S-nitrosoglutathione reductase (GSNOR), the enzyme that deactivates S-nitrosylation, is hypo-expressed in several human malignancies. Using multiple tumor models, we demonstrate that GSNOR deficiency induces S-nitrosylation of focal adhesion kinase 1 (FAK1) at C658. This event enhances FAK1 autophosphorylation and sustains tumorigenicity by providing cancer cells with the ability to survive in suspension (evade anoikis). In line with these results, GSNOR-deficient tumor models are highly suscep-tible to treatment with FAK1 inhibitors. Altogether, our findings advance our understanding of the oncogenic role of S-nitrosylation, define GSNOR as a tumor suppressor, and point to GSNOR hypo-expression as a ther-apeutically exploitable vulnerability in cancer.File | Dimensione | Formato | |
---|---|---|---|
Cell Rep 2023.pdf
accesso aperto
Tipologia:
Versione Editoriale (PDF)
Licenza:
Creative commons
Dimensione
9.44 MB
Formato
Adobe PDF
|
9.44 MB | Adobe PDF | Visualizza/Apri |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.