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Biochemical and cellular characterization of the interplay between glutamine metabolism, mTOR and Notch1 signaling in cancer therapy

Abstract : Tumorigenesis is a multistep process, consisting of genetic alterations that drive the malignant transformation of normal human cells. During this transformation, different oncogenic pathways are upregulated. mTORC1 and Notch1 signaling are well-known oncogenic pathways which play a central role in the regulation of cell growth and metabolism. Anti-mTORC1 and Notch1 therapies are approved as cancer treatments for several types of tumor but there are still developed resistances and relapse diseases. Thus, the main aim of this work is to study the inhibition of mTORC1 and Notch1 signaling pathway in cancer cells in order to design new therapeutic anti-cancer strategies. In the first place, we reported new class of mTORC1 inhibitors which has cytotoxicity specifically towards cancer cells. We demonstrated that ICSN3250, an analogue of the cytotoxic marine alkaloid halitulin, inhibited mTORC1 and induced cell death. The molecular mechanism of this inhibition is based on the displacement of the lipid phosphatidic acid, an activator of mTORC1 complex, from the FRB domain of mTOR protein. At the second stage, we have studied the connection between glutamine metabolism and Notch1 signaling in T-cell acute lymphoblastic leukemia (TALL). Metabolic changes in cancer cells are advantageous for rapid cell proliferation and tumor growth. We have generated Notch1-driven T-ALL cells and analyzed the consequences of Notch1 activation on glutamine metabolism. Indeed, under glutamine withdrawal, Notch1 upregulation induced apoptotic cell death by disrupting the accumulation of glutamine synthetase, a glutamine producing-enzyme. Overall, this thesis work allowed to describe new strategies to target mTORC1 and Notch1 pathways in cancer, which need future investigations to study their efficacy in therapies.
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Tra Ly Nguyen. Biochemical and cellular characterization of the interplay between glutamine metabolism, mTOR and Notch1 signaling in cancer therapy. Human health and pathology. Université de Bordeaux, 2018. English. ⟨NNT : 2018BORD0053⟩. ⟨tel-02887084⟩

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