Rizza Salvatore, Di Leo Luca, Pecorari Chiara, Giglio Paola, Faienza Fiorella, Montagna Costanza, Maiani Emiliano, Puglia Michele, Bosisio Francesca M, Petersen Trine Skov, Lin Lin, Rissler Vendela, Viloria Juan Salamanca, Luo Yonglun, Papaleo Elena, De Zio Daniela, Blagoev Blagoy, Filomeni Giuseppe
Redox Biology, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
Melanoma Research Team, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
Cell Rep. 2023 Jan 31;42(1):111997. doi: 10.1016/j.celrep.2023.111997. Epub 2023 Jan 18.
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 sustaining 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 susceptible 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 therapeutically exploitable vulnerability in cancer.
肿瘤微环境中的一氧化氮（NO）生成是癌症中的一个常见因素。S-亚硝基化，即NO对半胱氨酸的翻译后修饰，正成为维持肿瘤发生的关键转导机制。然而，大多数受S-亚硝基化调节的癌蛋白仍然未知。在这里，我们表明，使S-亚硝基化失活的酶S-亚硝基谷胱甘肽还原酶（GSNOR）在几种人类恶性肿瘤中低表达。使用多种肿瘤模型，我们证明GSNOR缺陷会诱导粘着斑激酶1（FAK1）在C658位点发生S-亚硝基化。这一事件增强了FAK1的自磷酸化，并通过赋予癌细胞在悬浮状态下存活（逃避失巢凋亡）的能力来维持肿瘤发生能力。与这些结果一致，GSNOR缺陷的肿瘤模型对FAK1抑制剂治疗高度敏感。总之，我们的发现推进了我们对S-亚硝基化致癌作用的理解，将GSNOR定义为一种肿瘤抑制因子，并指出GSNOR低表达是癌症中可用于治疗的一个弱点。
