Exploring the relationship between anastasis and mitochondrial ROS-mediated ferroptosis in metastatic chemoresistant cancers: a call for investigation

Abstract

Ferroptosis induces significant changes in mitochondrial morphology, including membrane condensation, volume reduction, cristae alteration, and outer membrane rupture, affecting mitochondrial function and cellular fate. Recent reports have described the intrinsic cellular iron metabolism and its intricate connection to ferroptosis, a significant kind of cell death characterized by iron dependence and oxidative stress regulation. Furthermore, updated molecular insights have elucidated the significance of mitochondria in ferroptosis and its implications in various cancers. In the context of cancer therapy, understanding the dual role of anastasis and ferroptosis in chemoresistance is crucial. Targeting the molecular pathways involved in anastasis may enhance the efficacy of ferroptosis inducers, providing a synergistic approach to overcome chemoresistance. Research into how DNA damage response (DDR) proteins, metabolic changes, and redox states interact during anastasis and ferroptosis can offer new insights into designing combinatorial therapeutic regimens against several cancers associated with stemness. These treatments could potentially inhibit anastasis while simultaneously inducing ferroptosis, thereby reducing the likelihood of cancer cells evading death and developing resistance to chemotherapy. The objective of this study is to explore the intricate interplay between anastasis, ferroptosis, EMT and chemoresistance, and immunotherapeutics to better understand their collective impact on cancer therapy outcomes. We searched public research databases including google scholar, PubMed, relemed, and the national library of medicine related to this topic. In this review, we discussed the interplay between the tricarboxylic acid cycle and glycolysis implicated in modulating ferroptosis, adding complexity to its regulatory mechanisms. Additionally, the regulatory role of reactive oxygen species (ROS) and the electron transport chain (ETC) in ferroptosis has garnered significant attention. Lipid metabolism, particularly involving GPX4 and System Xc- plays a significant role in both the progression of ferroptosis and cancer. There is a need to investigate the intricate interplay between anastasis, ferroptosis, and chemoresistance to better understand cancer therapy clinical outcomes. Integrating anastasis, and ferroptosis into strategies targeting chemoresistance and exploring its potential synergy with immunotherapy represent promising avenues for advancing chemoresistant cancer treatment. Understanding the intricate interplay among mitochondria, anastasis, ROS, and ferroptosis is vital in oncology, potentially revolutionizing personalized cancer treatment and drug development.

Keywords: EMT; anastasis; chemoresistance; ferroptosis; mitochondria.

Figure 1

Schematic depiction of ferroptosis and systemic toxicities. Ferroptosis plays a pivotal role in several diseases across different organs. Ferroptosis has significant implications in the pathophysiology of chemoresistance and the development of cancer stem cells (CSCs), which yet require future studies in chemoresistant cancers (?). In the liver, it contributes to the development and progression of hepatocellular carcinoma, liver fibrosis, and ischemia-reperfusion injury. Within the cardiovascular system, it is implicated in ischemia reperfusion injury, transplantation, and atherosclerosis. Gastrointestinal system disorders, including gastric cancer and colorectal cancer, are influenced by ferroptosis. In the pancreas, it is associated with pancreatic cancer and type I diabetes mellitus. In the kidney, ferroptosis is involved in acute kidney injury, ischemia-reperfusion injury, and clear cell renal cell carcinoma. Lung diseases, such as lung cancer and acute lung injury, typically have ferroptosis-mediated pathophysiology. Hematological malignancies in the blood system and the suppression of T- cell immunological function in the immune system are also associated with ferroptosis.

Figure 2

Mitochondria, iron metabolism, and ferroptosis. The diagram depicts the intricate series of events involved in iron metabolism within the human body, alongside ferroptosis, a form of regulated cell death. Initially, dietary iron, predominantly in the Fe(III) state, undergoes a sequence of conversions and transport processes. These processes include its reduction to Fe(II) within the intestinal environment, uptake by small intestinal epithelial cells, sequestration within the labile iron pool, extracellular release facilitated by ferroportin, and subsequent re-oxidation mediated by hephaestin. Subsequently, iron complexes with transferrin (TF), form transferrin-bound iron, which circulates in the bloodstream. TBI is internalized by cells via endocytosis, where it undergoes reduction to Fe(II) and enters the cellular cytoplasm. A fraction of the Fe(II) is stored within ferritin, while the remaining is reincorporated into the LIP. Heme, another significant iron source, follows a comparable pathway. Additionally, non-transferrin-bound iron from various tissues penetrates cells and is sequestered within the LIP. Furthermore, an additional reservoir of LIP is replenished through ferritinophagy, regulated by nuclear receptor coactivator 4. Intracellular free Fe(II) gains access to mitochondria via MFRN1 and undergoes subsequent biochemical transformations, ultimately leading to the onset of ferroptosis. Furthermore, ferroptosis is characterized by its dependence on iron and lipotoxicity. It operates by suppressing the activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4), resulting in the accumulation of lipid hydroperoxides. Genetically, multiple genes modulate ferroptosis. Unlike other types of cell death characterized by extracellular manifestations, ferroptosis primarily unfolds intracellularly. This leads to distinctive cellular alterations, including reduced mitochondrial size, heightened membrane density, damaged cristae, fragmentation of the outer membrane without compromising the cell membrane, and minimal changes in nuclear morphology without chromatin condensation. Biochemically, the deficiency in peroxidation repair capacity primarily originates from the impairment of the phospholipid peroxidase GPX4. This deficiency triggers the acquisition of reactive iron and the oxidation of phospholipids containing polyunsaturated fatty acids (PUFA), ultimately inducing ferroptosis. The decrease in intracellular antioxidant capacity exacerbates lipid ROS accumulation, and cause cellular ferroptosis. Glutathione peroxidase is influenced by various pathways, including the XC−/GSH/GPX4 system, and the ACSL4/LPCAT3/15-LOX and FSP1/CoQ10/NAD(P)H pathways.

Figure 3

System Xc- and lipid metabolism. System Xc- is a transmembrane transporter composed of SLC3A2 and SLC7A11 (xCT) proteins. It transports intracellular glutamate and extracellular cystine, which is converted into cysteine. Cysteine plays a pivotal role in synthesizing the antioxidant glutathione. Glutathione exists mainly in reduced (GSH) and oxidized (GSSG) forms, maintained in balance by various mechanisms. GPX4, a selenoprotein, converts glutathione to GSSG and efficiently reduces phospholipid peroxides while decomposing H₂O₂. GPX4 also inhibits arachidonic acid activation and lipid peroxidation (ROS). Long-chain acyl-CoA synthetase 4 (ACSL4) activates arachidonic acid and adrenic acid into their CoA forms, promoting the activation of polyunsaturated fatty acids (PUFA) mediated by LPCAT3. Intracellular Fe(II) undergoes the Fenton reaction with H₂O₂, generating hydroxyl radicals (OH·), contributing to lipid peroxidation and ROS production, causing cell membrane damage. Note: The complete pathways explanation was given in subheading 3.

Figure 4

Schematic depiction of genomic variations within genes regulating apoptosis are evident in cancer and contribute to the activation of pro-proliferation and pro-survival pathways, leading to apoptosis resistance. Upper Panel: While apoptosis has traditionally been regarded as irreversible, emerging evidence suggests its potential reversibility, termed anastasis, wherein cells can escape apoptotic signals even after reaching advanced stages. Anastasis poses challenges for chemotherapy development and utilization. This figure demonstrates the multifaceted role of survival mechanisms, metastasis, epithelial-mesenchymal transition (EMT), and DNA damage repair in facilitating anastasis, and the mechanistic interplay between ferroptosis reversal and anastasis to modulate chemoresistance, (?) emphasizing its implications for drug resistance and therapeutic strategies. Lower Panel: A proposed model illustrates the reversal of ferroptosis, and the interplay between pro-ferroptosis reversal pathways and pro-ferroptosis pathways is discussed. The schematic representation depicts structural and molecular changes during anastasis, showing cancer cells recovering from apoptosis by activating anastasis and acquiring mesenchymal features and molecular alterations promoting survival, metastasis, and angiogenesis. Genes associated with anastasis-mediated drug resistance, including ATF3, c-FOS, c-JUN, INBHA, SNAIL-1, ANGPTL4, and SOX-9, are highlighted. Cells recovering from apoptosis through anastasis exhibit pronounced structural changes, alter focal adhesion kinases, activate genes related to the actin cytoskeleton, and elevate proteins associated with chemoresistance. In addition, the interplay between the anastasis, and mitochondrial-ROS modulated ferroptosis proposed mechanisms should be explored to demonstrate the underlying mechanisms pertinent to chemoresistance with anastasis, and ferroptosis reversal (178, 250).