University thesis:
Dissertation, Friedrich-Schiller-Universität Jena, 2023
Footnote:
Tag der Verteidigung: 12.01.2023
Zusammenfassungen in deutscher und englischer Sprache
Description:
Metabolic reprogramming, which is usually referred to as glucose and lipid metabolism and intracellular redox homeostasis, is critical for aberrant proliferation, malignant progress, distal organ metastasis, and therapy efficacy of multiple tumors [1]. Albeit the encouraging findings of molecular participants and signaling pathways which, to some extent, dictate the acquisition of cancer-associated metabolic reprogramming, the casual relationship between metabolic reprogramming and tumor initiation is still elusive [2]. Isocitrate dehydrogenase 1 (IDH1) converts isocitrate to alpha-ketoglutarate (α-KG) and generates NADPH from NADP+. However, less is known of the mechanism underlying the regulation of IDH1 in cancer development. In this project, I discovered a novel function of deacetylase Sirtuin 7 (SIRT7), which regulates IDH1 expression in a deacetylase-independent but transcriptional factor sterol regulatory element-binding protein 1 (SREBP1) -dependent manner in cancer cells, by which SIRT7 couples metabolic reprogramming and epigenetically modifications via regulating α-KG levels. Besides, I found that miR-155-5p binds to the 3’ untranslated region (3’UTR) of IDH1 mRNA to suppress its expression. As effective drug candidates to reduce tumor load and therapy resistance, ferroptosis inducers were also studied in my second part of the thesis. Here, I found that Chlorido[N,N′-disalicylidene-1,2-phenylenediamine]iron(III) (iron(III) salophene) complexes triggered ferroptotic cell death and tremendously raised the levels of PL hydroperoxides. Mechanistically, iron(III) salophene complexes effectively catalyze hydrogen peroxide-dependent oxidation, apparently without releasing (free) hydroxyl radicals, as suggested from their failure to hydroxylate a small molecule sensor. In summary, iron(III) salophene complexes catalyze redox reactions and trigger ferroptosis by inducing PL peroxidation (potentially through indirect mechanisms).