bims-rehoca Biomed News
on Redox homeostasis in cancer
Issue of 2021–12–05
eightteen papers selected by
Vittoria Raimondi, Veneto Institute of Oncology



  1. Curr Cancer Drug Targets. 2021 Dec 01.
      Ferroptosis is a non-apoptotic mode of Regulated Cell Death (RCD) driven by excessive accumulation of toxic lipid peroxides and iron overload. Ferroptosis could be triggered by inhibiting the antioxidant defense system and accumulating iron-dependent Reactive Oxygen Species (ROS) that react with polyunsaturated fatty acids in abundance. Emerging evidence over the past few years has revealed that ferroptosis is of great potential in inhibiting growth and metastasis and overcoming tumor cell resistance. Thus, targeting this form of cell death could be perceived as a potentially burgeoning approach in cancer treatment. This review briefly presents the underlying mechanisms of ferroptosis and further aims to discuss various types of existing drugs and natural compounds that could be potentially repurposed for targeting ferroptosis in tumor cells. This, in turn, will provide critical perspectives on future studies concerning ferroptosis-based cancer therapy.
    Keywords:  Ferroptosis; antioxidant; cancer therapy; cell death; iron; pharmacotherapy; reactive oxygen species
    DOI:  https://doi.org/10.2174/1568009621666211202091523
  2. Mater Horiz. 2021 Aug 01. 8(8): 2273-2285
      A piezo-photocatalytic therapy based on thermally treated natural sphalerite nanosheet (NSH700 NS) heterojunction was applied to efficiently induce intracellular ROS burst and apoptosis of cancer cells. Upon ultrasound and laser irradiation, the formation of a polarized electric field and band bending of NSH700 NSs allow the directional separation of charges both in the bulk and their interface, thereby minimizing the probability of charge recombination. The piezo-photocatalytic effect leads to an efficient catalytic performance, exhibiting high-performance superoxide radical (˙O2-) and hydroxyl radical (˙OH) generation and glutathione (GSH) depletion, which results in a intracellular ROS burst-triggered apoptosis of cancer cells both in vitro and in vivo.
    DOI:  https://doi.org/10.1039/d1mh00492a
  3. Anticancer Res. 2021 Dec;41(12): 6051-6059
       BACKGROUND/AIM: In pancreatic cancer tissues, hypoxic areas exist due to poor blood flow. Attenuation of the pharmacological efficacy of existing anticancer drugs in these hypoxic areas necessitates the search for novel anticancer compounds. We aimed to determine whether erastin exhibits anticancer effects in a hypoxic environment.
    MATERIALS AND METHODS: Pancreatic cancer cell lines were subjected to cobalt chloride, a hypoxia-mimicking agent. Cell viability assay, measurement of reactive oxygen species, and western blotting analysis were conducted to investigate the efficacy of erastin under hypoxic environments.
    RESULTS: Erastin exhibited remarkable cytotoxicity and induced apoptosis under hypoxic conditions. Furthermore, erastin triggered the intracellular accumulation of reactive oxygen species in a hypoxic environment. Subsequent treatment with N-acetylcysteine, an antioxidant, markedly attenuated cytotoxicity, and apoptosis.
    CONCLUSION: Erastin induces cell death by accumulation of intracellular reactive oxygen species and inducing apoptosis under hypoxic conditions, proving its potential for further development as a novel anticancer compound.
    Keywords:  Apoptosis; erastin; hypoxia; pancreatic cancer; reactive oxygen species
    DOI:  https://doi.org/10.21873/anticanres.15424
  4. Front Oncol. 2021 ;11 768758
      Electromagnetic fields (EMF) raise intracellular levels of reactive oxygen species (ROS) that can be toxic to cancer cells. Because weak magnetic fields influence spin state pairing in redox-active radical electron pairs, we hypothesize that they disrupt electron flow in the mitochondrial electron transport chain (ETC). We tested this hypothesis by studying the effects of oscillating magnetic fields (sOMF) produced by a new noninvasive device involving permanent magnets spinning with specific frequency and timing patterns. We studied the effects of sOMF on ETC by measuring the consumption of oxygen (O2) by isolated rat liver mitochondria, normal human astrocytes, and several patient derived brain tumor cells, and O2 generation/consumption by plant cells with an O2 electrode. We also investigated glucose metabolism in tumor cells using 1H and 13C nuclear magnetic resonance and assessed mitochondrial alterations leading to cell death by using fluorescence microscopy with MitoTracker™ and a fluorescent probe for Caspase 3 activation. We show that sOMF of appropriate field strength, frequency, and on/off profiles completely arrest electron transport in isolated, respiring, rat liver mitochondria and patient derived glioblastoma (GBM), meningioma and diffuse intrinsic pontine glioma (DIPG) cells and can induce loss of mitochondrial integrity. These changes correlate with a decrease in mitochondrial carbon flux in cancer cells and with cancer cell death even in the non-dividing phase of the cell cycle. Our findings suggest that rotating magnetic fields could be therapeutically efficacious in brain cancers such as GBM and DIPG through selective disruption of the electron flow in immobile ETC complexes.
    Keywords:  cancer; diffuse intrinsic pontine glioma; electron transport chain; oxygen consumption; radical pair mechanism
    DOI:  https://doi.org/10.3389/fonc.2021.768758
  5. Phytother Res. 2021 Nov 30.
      Alnustone, a diarylheptane compound, exhibits potent growth inhibition against hepatocellular carcinoma (HCC) BEL-7402 cells. However, the underlying mechanisms associated with its anticancer activity remain unknown. In the present study, we evaluated the anticancer effect of alnustone against several human cancers focused on HCC and the possible associated mechanisms. The results showed that alnustone significantly inhibited the growth of several cancer cells by CCK-8 assay. Alnustone markedly induced apoptosis and decreased mitochondrial membrane potential in BEL-7402 and HepG2 cells. Alnustone inhibited the expression of proteins related to apoptosis and PI3K/Akt/mTOR/p70S6K pathways and generated ROS production in BEL-7402 and HepG2 cells. Moreover, N-acetyl-L-cysteine (NAC, a ROS inhibitor) could significantly reverse the effects of alnustone on the growth inhibition of BEL-7402 and HepG2 cells and the expression of proteins related to apoptosis and PI3K/Akt/mTOR signaling pathway in HepG2 cells. Furthermore, alnustone significantly inhibited tumor growth of HepG2 xenografts, obviously induced apoptosis in the tumor tissues and improved the pathological condition of liver tissues of mice in vivo. The study provides evidence that alnustone is effective against HCC via ROS-mediated PI3K/Akt/mTOR/p70S6K pathway and the compound has the potential to be developed as a novel anticancer agent for the treatment of HCC clinically.
    Keywords:  PI3K/Akt/mTOR/p70S6K signaling pathway; alnustone; human hepatocellular carcinoma; reactive oxygen species
    DOI:  https://doi.org/10.1002/ptr.7337
  6. Anticancer Res. 2021 Dec;41(12): 5881-5902
      Cancer remains the second leading cause of death worldwide. Research is currently focused on finding novel anticancer therapies and elucidating their mechanisms of action. Cellular redox balance is a promising target for new therapies, as cancer cells already have elevated levels of oxidizing agents due to hypermetabolism and genetic instability. Although free radicals are actively involved in vital cellular signaling pathways, they have also been implicated in certain diseases, including cancer. The aim of this review was to highlight the involvement of oxidative stress in the mechanism of action of anticancer agents. The difference in cellular redox balance between normal and cancer cells is discussed as a potential anticancer target, along with various examples of approved or experimental drugs that may alter the redox state. These drugs are presented in relation to their pro-oxidant or antioxidant mechanisms, with the consequent goal of underscoring the importance of such mechanisms in the overall efficacy of anticancer drugs.
    Keywords:  Free radicals; ROS; anticancer drugs; antioxidants; cancer; oxidative stress; pro-oxidants; redox homeostasis; review
    DOI:  https://doi.org/10.21873/anticanres.15408
  7. J Control Release. 2021 Nov 29. pii: S0168-3659(21)00636-2. [Epub ahead of print]
      Disulfiram (DSF), a familiar FDA-approved drug used for alcohol withdrawal, has recently been verified with potent antitumor therapeutic effect by generating Cu(DTC)2, which is the complex of its metabolite diethyldithiocarbamate (DTC) and copper. However, its poor tumor selectivity and insufficient endogenous Cu2+ concentration within tumor site largely hinders the application of DSF-based antitumor therapy. Therefore, a GSH-responsive coordination nanoparticles (Cu-IXZ@DSF) was established as a copper carrier to achieve synchronous but separate delivery of Cu2+ and DSF without antitumor ability, further to realize selectively triggered tumor in situ Cu(DTC)2 generation for antitumor therapy. A widely-used proteasome inhibitor ixazomib (IXZ) was chosen as ligands and Cu2+ was used as coordination nodes to form nanosized Cu-IXZ@DSF. The DSF encapsulated in Cu-IXZ@DSF could be reduced to DTC by intracellular GSH, which could contend for Cu2+ and realize in situ high toxic Cu(DTC)2 generation. Meanwhile, the chelation could lead to the disassembly of Cu-IXZ@DSF and release of IXZ to eventually achieve tumor specific "transformation from low toxicity to high toxicity" chemotherapy. The results of in vitro and in vivo experiments demonstrated that the as-prepared nanoplatform Cu-IXZ@DSF showed good biosafety and excellent antitumor effect via endoplasmic reticulum stress (ERS) as well as reactive oxygen species (ROS) generation pathway. Therefore, this nanocarrier provides an inspiring strategy with specific-triggered antitumor Cu(DTC)2 generation for DSF-based chemotherapy with high therapeutic effect and biosafety and showing great potential of treating cancer.
    Keywords:  Cu(DTC)(2); Disulfiram; Disulfiram-based chemotherapy; Glutathione; Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1016/j.jconrel.2021.11.041
  8. Biomed Res Int. 2021 ;2021 9142364
       Background: Cancer stem cells (CSCs) are responsible for tumorigenesis, chemoresistance, and metastasis. Chemoresistance is a major challenge in the management of lung cancer. Glutathione-sulphur-transferase-π (GST-π) plays an important role in the origin and development of various types of cancer by regulating the cellular redox balance. Recent investigations have demonstrated that GST-π is associated with the chemoresistance of lung CSCs (LCSCs). However, the mechanism of GST-π in lung cancer, particularly in LCSCs, remains unclear. The present study is aimed at exploring the potential role of GST-π in stemness and cisplatin (DDP) resistance of LCSCs. Materials and methods. In the present study, lung cancer cell spheres were established using the A549 cell line, which according to our previous research, was confirmed to exhibit characteristics of stem cells. Next, GST-π protein expression, apoptosis percentage, and intracellular reactive oxygen species (ROS) concentration in A549 adherent cells and A549 cell spheres were analyzed by western blotting and flow cytometry, respectively. Finally, DDP resistance, ROS concentration, and GST-π expression in LCSCs were analyzed following the interference with GST-π using DL-buthionine-(S,R)-sulphoximine and N-acetylcysteine.
    Results: The results revealed that GST-π was highly expressed in A549 cell spheres compared with A549 adherent cells and was associated with a decreased intracellular ROS concentration (both P < 0.05). Regulating GST-π protein expression could alter DDP resistance of LCSCs by influencing ROS.
    Conclusion: These results suggested that GST-π may be important for LCSC drug resistance by downregulating ROS levels. These findings may contribute to the development of new adjuvant therapeutic strategies for lung cancer.
    DOI:  https://doi.org/10.1155/2021/9142364
  9. World J Gastrointest Oncol. 2021 Nov 15. 13(11): 1668-1679
      Pancreatic cancer is a highly lethal malignancy with low resection and survival rates and is not sensitive to radiotherapy and chemotherapy. Ferroptosis is a novel form of nonapoptotic regulated cell death characterized by the accumulation of lipid peroxides and reactive oxygen species involved in iron metabolism. Ferroptosis has a significant role in the occurrence and development of various tumors. Previous studies have shown that regulating ferroptosis-induced cell death inhibited tumor growth in pancreatic cancer and was synergistic with other antitumor drugs to improve treatment sensitivity. Herein, we discuss the mechanism, inducers, and developments of ferroptosis in pancreatic cancer to provide new strategies for the treatment of the malignancy.
    Keywords:  Ferroptosis; Iron metabolism; Lipid peroxides; Pancreatic cancer; Reactive oxygen species
    DOI:  https://doi.org/10.4251/wjgo.v13.i11.1668
  10. Sci China Life Sci. 2021 Nov 26.
      The changes associated with malignancy are not only in cancer cells but also in environment in which cancer cells live. Metabolic reprogramming supports tumor cell high demand of biogenesis for their rapid proliferation, and helps tumor cell to survive under certain genetic or environmental stresses. Emerging evidence suggests that metabolic alteration is ultimately and tightly associated with genetic changes, in particular the dysregulation of key oncogenic and tumor suppressive signaling pathways. Cancer cells activate HIF signaling even in the presence of oxygen and in the absence of growth factor stimulation. This cancer metabolic phenotype, described firstly by German physiologist Otto Warburg, insures enhanced glycolytic metabolism for the biosynthesis of macromolecules. The conception of metabolite signaling, i.e., metabolites are regulators of cell signaling, provides novel insights into how reactive oxygen species (ROS) and other metabolites deregulation may regulate redox homeostasis, epigenetics, and proliferation of cancer cells. Moreover, the unveiling of noncanonical functions of metabolic enzymes, such as the moonlighting functions of phosphoglycerate kinase 1 (PGK1), reassures the importance of metabolism in cancer development. The metabolic, microRNAs, and ncRNAs alterations in cancer cells can be sorted and delivered either to intercellular matrix or to cancer adjacent cells to shape cancer microenvironment via media such as exosome. Among them, cancer microenvironmental cells are immune cells which exert profound effects on cancer cells. Understanding of all these processes is a prerequisite for the development of a more effective strategy to contain cancers.
    Keywords:  cancer immunology; cancer metabolism; cancer microenvironment; epigenetics
    DOI:  https://doi.org/10.1007/s11427-021-1999-2
  11. Cell Rep. 2021 Nov 30. pii: S2211-1247(21)01555-2. [Epub ahead of print]37(9): 110069
      Cancer cells utilize rapidly elevated cellular antioxidant programs to accommodate chemotherapy-induced oxidative stress; however, the underlying mechanism remains largely unexplored. Here we screen redox-sensitive effectors as potential therapeutic targets for colorectal cancer (CRC) treatment and find that cyclophilin A (CypA) is a compelling candidate. Our results show that CypA forms an intramolecular disulfide bond between Cys115 and Cys161 upon oxidative stress and the oxidized cysteines in CypA are recycled to a reduced state by peroxiredoxin-2 (PRDX2). Furthermore, CypA reduces cellular reactive oxygen species levels and increases CRC cell survival under insults of H2O2 and chemotherapeutics through a CypA-PRDX2-mediated antioxidant apparatus. Notably, CypA is upregulated in chemoresistant CRC samples, which predicts poor prognosis. Moreover, targeting CypA by cyclosporine A exhibits promising efficacy against chemoresistant CRC when combined with chemotherapeutics. Collectively, our findings highlight CypA as a component of cellular noncanonical antioxidant defense and as a potential druggable therapeutic target to ameliorate CRC chemoresistance.
    Keywords:  CRC; CypA; PRDX2; ROS; antioxidant system; colorectal cancer; disulfide bond; drug resistance; oxidative stress; reactive oxygen species; redox modification; redox signaling
    DOI:  https://doi.org/10.1016/j.celrep.2021.110069
  12. Small. 2021 Dec 02. e2103528
      Sonodynamic therapy as a promising noninvasive modality is being developed for tumor therapy, but there is a lack of next-generation sonosensitizers that can generate full ROS at high yields and simultaneously deplete elevated levels of glutathione (GSH) in tumor cells. Semiconductor p-n junctions are engineered as high-efficacy sonosensitizers for sonodynamic tumor eradication using pyridine N-doped carbon dots (N-CDs) as a p-type semiconductor and oxygen-deficient TiO2- x nanosheets as a n-type semiconductor. The rate constants of 1 O2 and •OH generation by ultrasound-excited N-CD@TiO2- x p-n junctions are 4.3 and 4.5 times higher than those of TiO2 , respectively. A Z-scheme carrier migration mechanism in the p-n junction achieving the rapid spatial separation of the ultrasound-generated electron-hole pairs for enhanced full ROS production is proposed. GSH-cleavable, Pt-crosslinked, N-doped CD fluorescent probes to detect the presence of intracellular GSH are also constructed. A GSH-responsive, p-n junction platform (Pt/N-CD@TiO2- x ) with integrated GSH detection, GSH depletion, and enhanced sonodynamic performance is then assembled. Malignant tumors are completely eradicated without relapse via intravenous administration of low-dose Pt/N-CD@TiO2- x under ultrasound irradiation. This work substantiates the great potential of biocompatible, GSH-responsive p-n junctions as next-generation sonosensitizers via p-n junction-enhanced ROS generation and metal ion oxidation of intracellular GSH.
    Keywords:  Pt-crosslinked carbon dots; carbon dots; glutathione (GSH) depletion, glutathione (GSH) detection; p-n junctions; sonodynamic therapy
    DOI:  https://doi.org/10.1002/smll.202103528
  13. J Oncol. 2021 ;2021 9403333
      Here, through applying 2,6-bis(4'-carboxyl-phenyl)pyridine (H2L), a rigid ligand featuring both carboxylic acid and pyridine groups, a new coordination polymer containing Na(I) has been generated with the reaction between H2L ligand and NaNO3 in a water and DMF mixed solvent, and its chemical composition is [Na2L]n. Furthermore, the antiproliferative activity of Na(I) complex against the HXO-Rb44 retinoblastoma cells was detected with CCK-8 assay. Hoechst staining along with Annexin V-FITC/PI revealed that Na(I) complex induces the HXO-Rb44 retinoblastoma cells apoptosis. Flow cytometry analysis of reactive oxygen species (ROS) showed that Na(I) complex significantly increases the level of intracellular ROS. Importantly, western blot analysis revealed that Na(I) complex might induce apoptosis through inactivation of PI3K/AKT/mTOR pathway.
    DOI:  https://doi.org/10.1155/2021/9403333
  14. Indian J Pharmacol. 2021 Sep-Oct;53(5):53(5): 377-383
       INTRODUCTION: The use of natural resources as medicines for cancer therapies has been described throughout history in the form of traditional medicines. However, many resources are still unidentified for their potent biological activities. Clerodendrum viscosum is a hill glory bower reported as a remedy against oxidative stress, skin diseases, and intestinal infections.
    MATERIALS AND METHODS: We have collected the C. viscosum leaves and used for the preparation of 70% methanolic extract (CVLME). Then, CVLME has been confirmed for anticancer properties on various cancer cell lines by evaluating cytotoxicity, cell cycle analysis, induction of ROS and apoptosis, and nuclear fragmentation. Further, the phytochemical analysis of CVLME was evaluated through high-performance liquid chromatography.
    RESULTS: Cell proliferation assay revealed the selective cytotoxicity of CVLME against breast cancer cell line (MCF-7). The FACS-based cell cycle analysis showed increased subG1 (apoptosis) population dose dependently. Further, the apoptosis-inducing effect of CVLME was confirmed by annexin staining. Flow cytometry and confocal microscopy revealed the selective ROS generation upon CVLME treatment. The confocal-based morphological study also revealed condensed and fragmented nuclear structure in CVLME-treated MCF-7 cells. Phytochemical investigations further indicated the presence of tannic acid, catechin, rutin, and reserpine which might be the reason for the anticancer activity of CVLME.
    CONCLUSION: The above-combined results revealed the anticancer effect of CVLME, which may be due to the selective induction of ROS in breast carcinoma.
    Keywords:  70% methanolic extract; Clerodendrum viscosum; ROS induction; anticancer; medicinal plant
    DOI:  https://doi.org/10.4103/ijp.IJP_565_19
  15. J Lipid Res. 2021 Nov 24. pii: S0022-2275(21)00137-1. [Epub ahead of print] 100154
      Cancer cells can become dependent on exogenous serine, depletion of which results in slower growth and activation of a number of adaptive metabolic changes. We previously demonstrated that serine and glycine (SG) deprivation causes loss of sphingosine kinase 1 (SK1) in cancer cells, thereby increasing levels of its lipid substrate, sphingosine (Sph), which mediates several adaptive biological responses. However, the signaling molecules that regulate levels of SK1 and Sph in response to SG deprivation have yet to be defined. Here, we identify 1-deoxysphinganine (dSA), a non-canonical sphingoid base generated in the absence of serine from the alternative condensation of alanine and palmitoyl CoA by serine palmitoyl transferase (SPT), as a proximal mediator of SG deprivation in SK1 loss and Sph level elevation in SG deprivation in cancer cells. SG starvation markedly increased dSA levels in vitro and in vivo, and in turn induced SK1 degradation through a SPT-dependent mechanism, resulting in an increase in SPH levels. Addition of exogenous dSA caused a moderate increase in intracellular reactive oxygen species (ROS), which in turn decreased pyruvate kinase PKM2 activity while increasing phosphoglycerate dehydrogenase (PHGDH) levels, and thereby promoted serine synthesis. We further showed that increased dSA induces the adaptive cellular and metabolic functions in the response of cells to decreased availability of serine likely by increasing Sph levels. Thus, we conclude that dSA functions as an initial sensor of serine loss, SK1 functions as its direct target, and Sph functions as a downstream effector of cellular and metabolic adaptations. These studies define a previously unrecognized 'physiological' non-toxic function for dSA.
    Keywords:  Sphingosine kinase; hereditary sensory and autonomic neuropathy (HSAN); mass spectrometry; phosphoglycerate dehydrogenase (PHGDH); pyruvate kinase (PKM2); reactive oxygen species (ROS); serine biosynthesis; serine palmitoyl transferase (SPT); sphingosine; ubiquitination
    DOI:  https://doi.org/10.1016/j.jlr.2021.100154
  16. Antioxid Redox Signal. 2021 Nov 30.
       SIGNIFICANCE: The imbalance in redox homeostasis is known as oxidative stress, which is relevant to many diseases such as cancer, arteriosclerosis, and neurodegenerative disorders. Overproduction of reactive oxygen species (ROS) is one of the factors that trigger the redox state imbalance in vivo. ROS have high reactivity and impair biomolecules, while antioxidants and antioxidant enzymes, such as ascorbate and glutathione, reduce the overproduction of ROS to rectify the redox imbalance. Owing to this, redox monitoring tools have been developed to understand the redox fluctuations in oxidative stress-related diseases. Recent Advances: In an attempt to monitor redox substances, including ROS and radical species, versatile modalities have been developed, such as electron spin resonance, chemiluminescence, and fluorescence. In particular, many fluorescent probes have been developed that are selective for ROS. This has significantly contributed to understanding the relevance of ROS in disease onset and progression.
    CRITICAL ISSUES: To date, the dynamics of ROS and radical fluctuation in in vivo redox states remain unclear, and there are few methods for the in vivo detection of redox fluctuations.
    FUTURE DIRECTIONS: In this review, we summarize the development of radiolabeled probes for monitoring redox-relevant species by nuclear medical imaging that is applicable in vivo. In the future, translational research is likely to be advanced through the development of highly sensitive and in vivo applicable detection methods, such as nuclear medical imaging, to clarify the underlying dynamics of ROS, radicals, and redox substances in many diseases.
    DOI:  https://doi.org/10.1089/ars.2021.0246
  17. J Clin Biochem Nutr. 2021 Nov;69(3): 265-271
      Inflammation is a primary risk factor for cancer. Epidemiological studies previously demonstrated that aspirin decreased the incidence of cancer and specifically reduced the risk of colorectal cancer. However, the number of animal studies that have confirmed the efficacy of aspirin remains limited. Therefore, the purpose of the present study was to investigate the mechanisms by which aspirin prevents colorectal cancer in mice. ICR mice were treated with azoxymethane and the ulcerative colitis inducer, dextran sodium sulfate, to induce colorectal tumors. Aspirin was orally administered three times per week for 12 weeks. Aspirin significantly reduced the number and size of colorectal tumors. Aspirin also significantly decreased tumor necrosis factor alpha and reactive oxygen species (ROS) levels in the plasma. Immunohistochemical analyses and western blots showed that cyclooxygenase 2 (COX2), inducible nitric oxide synthase (iNOS), and the active form of Yes-associated protein 1 (YAP1), and cytosolic high mobility group box 1 (HMGB1) were strongly expressed at colorectal tumor sites and clearly suppressed by aspirin. An indicator of inflammation-related DNA damage, 8-nitroguanine, also accumulated in the colorectal tissues and was suppressed by aspirin. The present results suggest that the ingestion of aspirin suppressed carcinogenesis caused by inflammation through decreases in COX2 and ROS levels, resulting in reductions in DNA damage and oncogenic YAP1.
    Keywords:  8-nitroguanine; cyclooxygenase 2; inflammation; reactive oxygen species; yes-associated protein 1
    DOI:  https://doi.org/10.3164/jcbn.20-189
  18. FEBS J. 2021 Dec 01.
      Brother of Regulator of Imprinted Sites (BORIS) or CCCTC-Binding Factor Like (CTCFL) is a nucleotide-binding protein, aberrantly expressed in various malignancies. Expression of BORIS has been found to be associated with the expression of oncogenes which regulate the reactive oxygen species (ROS) biogenesis, DNA double-strand break repair, regulation of stemness, and induction of cellular senescence. In the present study, we have analyzed the effects of knockdown of BORIS, a potential oncogene, on the induction of senescence and tumor suppression. Loss of BORIS downregulated the expression of critical oncogenes such as BMI1, Akt, MYCN, and STAT3, whereas overexpression increased their respective expression levels in MYCN-amplified neuroblastoma cells. BORIS knockdown exhibited high levels of ROS biogenesis, indicating an upregulated mitochondrial superoxide production and thereby induction of senescence. Our study also showed that the loss of BORIS facilitated cellular senescence through the disruption of telomere integrity via altering the expression of various proteins required for telomere capping (POT1, TRF2, and TIN1). In addition to affecting ROS production and DNA damage, BORIS knockdown sensitized the cells towards chemotherapeutic drugs and induced apoptosis. Tumor induction studies on in-vivo xenograft mouse models showed that cells with loss of BORIS/CTCFL failed to induce tumors. From our study, we conclude that silencing BORIS/CTCFL influences tumor growth and proliferation by regulating key oncogenes. The results also indicated that the BORIS knockdown can cause cellular senescence and upon a combinatorial treatment with chemotherapeutic drugs can induce enhanced drug sensitivity in MYCN amplified neuroblastoma cells.
    Keywords:  BORIS/CTCFL; Cellular senescence; DNA damage; Drug-resistance; ROS
    DOI:  https://doi.org/10.1111/febs.16309