Potential Role of APEX1 During Ferroptosis

Abstract

Ferroptosis is a recently discovered category of programmed cell death. It is much different from other types of cell death such as apoptosis, necrosis and autophagy. The main pathological feature of ferroptosis is the accumulation of iron-dependent lipid peroxidation. The typical changes in the morphological features of ferroptosis include cell volume shrinkage and increased mitochondrial membrane area. The mechanisms of ferroptosis may be mainly related to lipid peroxidation accumulation, imbalance in amino acid antioxidant system, and disturbance of iron metabolism. Besides, hypoxia-inducible factor (HIF), nuclear factor-E2-related factor 2 (Nrf2), and p53 pathway have been demonstrated to be involved in ferroptosis. At present, the molecular mechanisms of ferroptosis pathway are still unmapped. In this review, an outlook has been put forward about the crucial role of apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) in the regulation of ferroptosis. APEX1 plays an important role in the regulation of intracellular redox balance and can be used as a potential inhibitor of ferroptotic cell death. Bioinformatics analysis indicated that the mRNA level of APEX1 is decreased in cases of ferroptosis triggered by erastin. Besides, it was found that there was a significant correlation between APEX1 and genes in the ferroptosis pathway. We have discussed the possibility to employ APEX1 inducers or inhibitors in the regulation of ferroptosis as a new strategy for the treatment of various human diseases.

GSH/APE1 Cascade-Activated Nanoplatform for Imaging Therapy Resistance Dynamics and Enzyme-Mediated Adaptive Ferroptosis

“…Interestingly, the fluorescence intensity of DCFH-DA increased with the increase of GAN concentration, suggesting that GAN could promote intracellular ROS generation (Figure d,e and Figure S22). Furthermore, Western blotting results showed that the APE1 level in HeLa cells gradually increased as the concentration increased (Figure f,g), which confirmed that the increase of intracellular oxygen stress could promote the APE1 expression within cancer cells. , …”

“…Adaptive therapy is an evolving and emerging paradigm that uses imaging information to update the therapy plan, instead of keeping one static mode throughout the whole course of therapy, affording a more accurate treatment of disease and allowing active treatment to delay the onset of treatment resistance. , During the ferroptosis process in the tumor, cancer cells could rapidly implement additional mitigation strategies to survive stress, leading to ineffective treatment when those cells are subjected to therapeutic stress induced by DNA damage or oxidation. ,− Interestingly, we discovered that persistent oxidative stress during ferroptosis could upregulate APE1 protein expression. Apurinic/apyrimidinic endonuclease 1 (APE1) is a key protein regulating cell response toward oxidative stress and DNA damage via two aspects: (1) activation of several transcription factors for balancing intracellular redox environment and reducing oxidative stress; (2) as the main enzyme to participate in the process of base excision repair (BER) for repairing damaged DNA. − Due to the APE1’s antioxidant and DNA repair functions, upregulated APE1 may counteract the overproduction of ROS and damage to DNA during ferroptosis, thereby decreasing the therapeutic effect, leading to a “ferroptosis resistance”.…”

“…Therefore, it is critical and meaningful to address the adverse effect of APE1 on ferroptosis therapy (APE1-mediated ferroptosis resistance). Moreover, since APE1 is associated with intracellular oxidative stress, − the monitoring of APE1 dynamics would reflect intracellular oxidative stress and LPO level during ferroptosis, which would be one of the key indicators for predicting therapy resistance and ferroptosis outcome, thus being beneficial for performing high-specificity and high-efficiency ferroptosis therapy . Although several kinds of DNA-based fluorescence probes were developed for measuring intracellular APE1, most of them were only used at the cellular level, rarely for monitoring APE1 activity in vivo. ,, And until now, no compatible APE1 probe and adapted imaging technology have been developed for monitoring the dynamics of APE1 during ferroptosis in a living system.…”

Cinnamaldehyde alleviates doxorubicin-induced cardiotoxicity by decreasing oxidative stress and ferroptosis in cardiomyocytes

“…Nrf2 signaling is closely correlated with ferroptosis [ 40 ], which exerts an important role in myocardial oxidative injury [ 41 , 42 ]. To assess the role of DOX and CA in ferroptosis, H9c2 cells were treated with DOX and CA, and then ferroptosis markers (iron concentration, ROS, MDA, and GSH levels) were examined.…”