CEEPC/IPM/CMSC - Abstrakt prezentace

(CEEPC/IPM/CMSC 2022 - FrO-20)
Redox resetting by modulation of redox sensor Kelch-like ECH-associated protein 1 restores leukemic cells sensitivity to Azacytidine

Kristýna Pimková 1 *, Lubomír Minařík 1, Michaela Myšáková 1, Juraj Kokavec 1, Tomáš Stopka 1

  1. BIOCEV, First Faculty of Medicine, Charles University, Czech Republic

Abstrakt

A hypomethylating drug 5-azacytidine (AZA) is used to treat patients with myeloid malignancies who are in a high risk of progression to leukemia. Although AZA significantly prolongs patient survival, the efficacy of treatment is often hampered by the early development of resistance. The mechanisms by which leukemic cells overcome AZA toxicity are not yet fully understood, but there is considerable evidence that the molecular events leading to the loss of response to AZA are driven by redox mechanisms. In this study, we focused on investigating the role of redox homeostasis in leukemic cell resistance to AZA.
We used a quantitative mass spectrometry-based proteomics approach to identify protein targets of oxidative modifications in a leukemia cell model of AZA resistance developed in our laboratory. Analysis showed that treatment of AZA-sensitive cells (AZA-S) resulted in altered cysteine oxidation in 20% of proteins (578 of 2853). We identified key cysteine sites of proteins that regulate apoptosis. We hypothesize that AZA-induced oxidative stress is a key factor in its cytotoxic effect. AZA resistance was associated with changes in the oxidative state of 14% of cysteine proteins involved in glutathione metabolism and the antioxidant defense system, such as the key redox sensor Kelch-like ECH-associated protein 1 (KEAP1). The data suggest that AZA-R are under chronic oxidative stress and have adapted to redox stressors. We show that inhibition of KEAP1 blocks redox adaptation and restores AZA-R cells' sensitivity to AZA.
In conclusion, we demonstrated that the mechanism of AZA resistance involves cellular adaptation to oxidative stress and that modulation of the KEAP1 cellular antioxidant response pathway can re-sensitize AZA-resistant cells in vitro.

* Korespondující autor: kristyna.pimkova@lf1.cuni.cz


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