Nitric oxide-dependent inflammation underlies Notch and PI3K/Akt oncogene cooperation
Nitric oxide-dependent inflammation underlies Notch and PI3K/Akt oncogene cooperation
Abstract Concurrent activating mutations of the Notch and PI3K/Akt signalling pathways cooperate in the induction of aggressive cancers. Unfortunately, direct targeting of any of these aberrant pathways can result in severe side effects due to their broad physiological roles in multiple organs. Here, using an unbiased chemical in vivo screen in Drosophila we identified compounds that suppress the activity of the pro-inflammatory enzymes, nitric oxide synthase (NOS) and lipoxygenase (LOX), capable to block oncogenic Notch-PI3K/Akt cooperation without unwanted side effects. Genetic inactivation of NOS and LOX signalling components mirrors the anti-tumorigenic effect of the hit compounds. We show that NOS activity and immunosuppression associated to inflammation facilitates Notch-mediated tumorigenesis. Our study reveals an unnoticed immune inflammatory process underlying Notch-PI3K/Akt tumours and exposes NOS as a druggable target for anti-cancer therapeutic development.
Mih¨￠ly J¨?zsef、Garc¨aa-Castillo Jes¨2s、Vallejos Diana Marcela、L¨?pez Lucia Garc¨aa、Villegas Santiago Nahuel、Dominguez Maria、Gombos Rita、P¨|rez Irene Guti¨|rrez、Ros Vanina Da
Institute of Genetics, Biological Research Centre HASInstituto de Neurociencias, Consejo Superior de Investigaciones Cient¨aficas (CSIC) and Universidad Miguel Hernandez (UMH)Instituto de Neurociencias, Consejo Superior de Investigaciones Cient¨aficas (CSIC) and Universidad Miguel Hernandez (UMH)Instituto de Neurociencias, Consejo Superior de Investigaciones Cient¨aficas (CSIC) and Universidad Miguel Hernandez (UMH)Instituto de Neurociencias, Consejo Superior de Investigaciones Cient¨aficas (CSIC) and Universidad Miguel Hernandez (UMH)Instituto de Neurociencias, Consejo Superior de Investigaciones Cient¨aficas (CSIC) and Universidad Miguel Hernandez (UMH)Institute of Genetics, Biological Research Centre HASInstituto de Neurociencias, Consejo Superior de Investigaciones Cient¨aficas (CSIC) and Universidad Miguel Hernandez (UMH)Instituto de Neurociencias, Consejo Superior de Investigaciones Cient¨aficas (CSIC) and Universidad Miguel Hernandez (UMH)
肿瘤学基础医学生物科学研究方法、生物科学研究技术
chemical screenCancerDrosophilaNotchPI3K/AktPteninflammationnitric oxide synthaselipoxygenases
Mih¨￠ly J¨?zsef,Garc¨aa-Castillo Jes¨2s,Vallejos Diana Marcela,L¨?pez Lucia Garc¨aa,Villegas Santiago Nahuel,Dominguez Maria,Gombos Rita,P¨|rez Irene Guti¨|rrez,Ros Vanina Da.Nitric oxide-dependent inflammation underlies Notch and PI3K/Akt oncogene cooperation[EB/OL].(2025-03-28)[2025-05-08].https://www.biorxiv.org/content/10.1101/174169.点此复制
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