Barbara Marengo
Josè Pedro Friedmann Angeli
Cinzia Domenicotti- 1Department of Experimental Medicine, General Pathology Section, University of Genoa, Genoa, Italy
- 2Rudolf Virchow Center for Integrative and Translational Bioimaging, Chair of Translational Cell Biology, University of Würzburg, Würzburg, Germany
Editorial on the Research Topic
Redox metabolism: a double edge sword sustaining the adaptive resistance to therapy in cancer
Metabolic reprogramming is a pivotal hallmark of cancer that contributes to therapy resistance (1). Cancer cells possess the remarkable ability to modify their metabolism, enabling them to regulate Reactive Oxygen Species (ROS) levels. Maintaining ROS at moderate levels facilitates cell survival and proliferation. Understanding the intricacies of cancer redox metabolism is crucial for identifying specific targets that can improve therapy efficacy. This Research Topic features three original research articles, two review articles, and one perspective article, which showcase recent advancements in this field. Collectively, these articles provide compelling evidence supporting the modulation of redox metabolism as a potent strategy to counteract adaptive resistance in cancer therapy.
In their review article, Min et al. delve into the intricate role of cysteine, both bound to and free from proteins, in cancer biology. Cysteine, an amino acid, participates in several metabolic pathways, including the synthesis of reduced glutathione (GSH), a major endogenous non-enzymatic antioxidant. Additionally, cysteine plays a crucial role in generating sulfur-containing biomolecules, such as hydrogen sulfide (H2S), taurine, coenzyme A, and biotin (2). Furthermore, the oxidation of cysteine residues in numerous phosphatases, kinases, and transcription factors can modulate their activities, impacting cancer cell survival and therapy resistance. Given the pro-oxidant nature of most chemotherapeutic drugs, there is a growing interest in developing covalent inhibitors that specifically target cysteine residues near the ATP-binding pocket of redox signaling proteins. Moreover, GSH has been widely acknowledged for its crucial role in cancer progression and therapy resistance (3–5). Pompella et al.‘s perspective article highlights the interaction of glycyl-cysteine, a dipeptide originating from GSH metabolism, with cisplatin. This interaction impedes cisplatin’s access to cancer cells, reducing its cytotoxic efficacy. GGT1 expression emerges as a significant biomarker for cisplatin resistance. Notably, cisplatin-induced effects are mediated by ROS overproduction and lipid peroxidation (6), underscoring the need to investigate GGT1’s potential to prevent ferroptosis, a form of programmed cell death induced by GSH depletion and resulting in peroxidation of membrane phospholipids (7, 8). The involvement of high intracellular GSH levels in therapy resistance is further confirmed by Garbarino et al.‘s original research article, demonstrating that BRAF-mutated metastatic melanoma cells develop resistance to PLX4032 (Vemurafenib), a BRAF inhibitor approved for melanoma treatment (9). This resistance is attributed to a metabolic rewiring of oxidative phosphorylation and the maintenance of pyruvate dehydrogenase activity. Leveraging an in vitro model of drug resistance derived from patient-isolated melanoma cells, the authors propose that inhibitors targeting GSH biosynthesis and/or pyruvate dehydrogenase activity, in combination with PLX4032, could overcome therapy resistance.
In response to mounting evidence implicating redox metabolism as a critical regulator of tumor progression and therapy response, Ji et al. have developed a novel constraint-based computational method, COSMro, to integrate redox signaling and metabolic networks. Applying this innovative approach to a head and neck cancer model of radiation resistance, the authors uncover a relationship between intracellular redox state and cholesterol metabolism. Intriguingly, their network analysis highlights pathways potentially contributing to radioresistance, including the activation of the phosphatidyl-inositol-3-kinase/protein kinase B (AKT) pathway and the rerouting of glycolysis into the pentose phosphate pathway (PPP) for generating essential molecules like nicotinamide adenine dinucleotide phosphate (NADPH) and nucleotide building blocks crucial for repairing radiation-induced DNA damage. Complementing this research, Goetting et al. found that the aberrant activation of AKT exerts an influence on cell metabolism, antioxidant defense, and radiosensitivity. The study reveals that cancer cells expressing the AKT variant (AKT-E17K) exhibit radioresistance correlated with enhanced GSH levels through novel GSH biosynthesis promotion and increased GSH regeneration via NADPH formation. Numerous studies have established the involvement of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in the antioxidant response and metabolic switch, which drives the adaptive response of cancer cells to chemo and radiotherapy (10–12). Inhibitors of Nrf2 have demonstrated their potential in sensitizing various types of cancer cells to these therapies. Fascinatingly, Oronsky et al. report on the triple action of RRx-001, a nonpolar small molecule that readily penetrates cell membranes and the blood-brain barrier. RRx-001 acts as an NLRP3 inflammasome inhibitor, nitric oxide superagonist, and Nrf2 inducer. It can switch between pro-oxidant/pro-inflammatory and antioxidant/anti-inflammatory activities, depending on the redox state and tissue oxygenation.
Collectively, the articles included in this Research Topic strengthen the pivotal role of redox metabolism in determining cancer cell resistance to therapy and although further studies are needed, we hope that information herein collected can be helpful to spark more effective and personalized anticancer strategies to improve patient’s outcome and survival. We would like to thank all the authors who have participated in the realization of this Research Topic and shared their knowledge and the latest results of their studies. Finally, we would like to thank the reviewers for objectively evaluating the submitted papers and the editorial staff for their kind support.
Author contributions
BM: Writing – original draft, Writing – review & editing, Writing – original draft, Writing – review & editing. JA: Writing – original draft, Writing – review & editing, Writing – original draft, Writing – review & editing. CD: Writing – original draft, Writing – review & editing, Writing – original draft, Writing – review & editing.
Funding
This research was financed by the University of Genova.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell (2011) 144:646–74. doi: 10.1016/j.cell.2011.02.013
2. Paul BD, Sbodio JI, Snyder SH. Cysteine metabolism in neuronal redox homeostasis. Trends Pharmacol Sci (2018) 39(5):513–24. doi: 10.1016/j.tips.2018.02.007
3. Colla R, Izzotti A, De Ciucis C, Fenoglio D, Ravera S, Speciale A, et al. Glutathione- mediated antioxidant response and aerobic metabolism: two crucial factors involved in determining the multi-drug resistance of high-risk neuroblastoma. Oncotarget (2016) 7:70715–37. doi: 10.18632/oncotarget.12209
4. Traverso N, Ricciarelli R, Nitti M, Marengo B, Furfaro AL, Pronzato MA, et al. Role of glutathione in cancer progression and chemoresistance. Oxid Med Cell Longev (2013) 2013:972913. doi: 10.1155/2013/972913
5. Pizzimenti S, Ribero S, Cucci MA, Grattarola M, Monge C, Dianzani C, et al. Oxidative stress-related mechanisms in melanoma and in the acquired resistance to targeted therapies. Antioxidants (2021) 10:1942. doi: 10.3390/antiox10121942
6. Tchounwou PB, Dasari S, Noubissi FK, Ray P, Kumar S. Advances in our understanding of the molecular mechanisms of action of cisplatin in cancer therapy. J Exp Pharmacol (2021) 13:303–28. doi: 10.2147/JEP.S267383
7. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell (2012) 149(5):1060–72. doi: 10.1016/j.cell.2012.03.042
8. Friedmann Angeli JP, Krysko DV, Conrad M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat Rev Cancer (2019) 19(7):405–14. doi: 10.1038/s41568-019-0149-1
9. Hallmeyer S, Gonzalez R, Lawson DH, Cranmer LD, Linette GP, Puzanov I, et al. 542 Vemurafenib treatment for patients with locally advanced, unresectable stage IIIC or metastatic melanoma and activating exon 15 BRAF mutations other than V600E. Melanoma Res (2017) 27:585–544 90. doi: 10.1097/CMR.0000000000000398
10. Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature (2009) 458(7239):780–3. doi: 10.1038/nature07733
11. Sharma PK, Varshney R. 2-deoxy-D-glucose and 6-aminonicotinamide-mediated nrf2 down regulation leads to radiosensitization of Malignant cells via abrogation of GSH-mediated defense. Free Radic Res (2012) 46(12):1446–57. doi: 10.3109/10715762.2012.724771
Keywords: metabolic reprogramming, redox signaling, antioxidants, chemoresistance, radioresistance, ferroptosis
Citation: Marengo B, Friedmann Angeli JP and Domenicotti C (2023) Editorial: Redox metabolism: a double edge sword sustaining the adaptive resistance to therapy in cancer. Front. Oncol. 13:1260233. doi: 10.3389/fonc.2023.1260233
Received: 17 July 2023; Accepted: 24 July 2023;
Published: 15 August 2023.
Edited and Reviewed by:
Michael P. Lisanti, University of Salford, United KingdomCopyright © 2023 Marengo, Friedmann Angeli and Domenicotti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Cinzia Domenicotti, Cinzia.Domenicotti@unige.it