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.
31-gen-2023
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/10 - BIOCHIMICA
English
CP: Cancer; CP: Molecular biology; CP: Molecular biology; FAK inhibitors; S-nitrosylation; SRC; anoikis; cancer; focal adhesion; nitric oxide; spheroids
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].
Rizza, S; Di Leo, L; Pecorari, C; Giglio, P; Faienza, F; Montagna, C; Maiani, E; Puglia, M; Bosisio, Fm; Petersen, Ts; Tian, L; Rissler, V; Viloria, J...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/321342
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