bims-nurfca 2024-04-07 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2024‒04‒07
eight papers selected by
Caner Geyik, Istinye University

Butyrate increases methylglyoxal production through regulation of the JAK2/Stat3/Nrf2/Glo1 pathway in castration‑resistant prostate cancer cells.
Esculin induces endoplasmic reticulum stress and drives apoptosis and ferroptosis in colorectal cancer via PERK regulating eIF2α/CHOP and Nrf2/HO-1 cascades.
Comprehensive analysis of IGF2BP3 with expression features, prognosis, immune modulation and stemness in hepatocellular carcinoma and pan-cancer.
Ononin triggers ferroptosis-mediated disruption in the triple negative breast cancer both in vitro and in vivo.
Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies.
Unlocking the anticancer activity of gambogic acid: a shift towards ferroptosis via a GSH/Trx dual antioxidant system.
Nobiletin alleviates cisplatin-induced ototoxicity via activating autophagy and inhibiting NRF2/GPX4-mediated ferroptosis.
Ivacaftor attenuates gentamicin-induced ototoxicity through the CFTR-Nrf2-HO1/NQO1 pathway.

Oncol Rep. 2024 May;pii: 71. [Epub ahead of print]51(5):

Butyrate increases methylglyoxal production through regulation of the JAK2/Stat3/Nrf2/Glo1 pathway in castration‑resistant prostate cancer cells.

Yi-Jan Hsia, Zhang-Min Lin, Taolan Zhang, Tz-Chong Chou.

  Cancer cells are characterized by increased glycolysis, known as the Warburg effect, which leads to increased production of cytotoxic methylglyoxal (MGO) and apoptotic cell death. Cancer cells often activate the protective nuclear factor erythroid 2‑related factor2 (Nrf2)/glyoxalase1 (Glo1) system to detoxify MGO. The effects of sodium butyrate (NaB), a product of gut microbiota, on Nrf2/Glos/MGO pathway and the underlying mechanisms in prostate cancer (PCa) cells were investigated in the present study. Treatment with NaB induced the cell death and reduced the proliferation of PCa cells (DU145 and LNCap). Moreover, the protein kinase RNA-like endoplasmic reticulum kinase/Nrf2/Glo1 pathway was greatly inhibited by NaB, thereby accumulating MGO-derived adduct hydroimidazolone (MG-H1). In response to a high amount of MGO, the expression of Nrf2 and Glo1 was attenuated, coinciding with an increased cellular death. NaB also markedly inhibited the Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (Stat3) pathway. Conversely, co‑treatment with Colivelin, a Stat3 activator, significantly reversed the effects of NaB on Glo1 expression, MG-H1 production, and the cell migration and viability. As expected, overexpression of Stat3 or Glo1 reduced NaB‑induced cell death. The activation of calcium/calmodulin dependent protein kinase II gamma and reactive oxygen species production also contributed to the anticancer effect of NaB. The present study, for the first time, demonstrated that NaB greatly increases MGO production through suppression of the JAK2/Stat3/Nrf2/Glo1 pathway in DU145 cells, a cell line mimicking castration‑resistant PCa (CRPC), suggesting that NaB may be a potential agent for PCa therapy.

Keywords:  butyrate; glyoxalases; methylglyoxal; nuclear factor erythroid 2‑related factor2; prostate cancer; signal transducer and activator of transcription 3

DOI:  https://doi.org/10.3892/or.2024.8730
J Ethnopharmacol. 2024 Mar 30. pii: S0378-8741(24)00438-0. [Epub ahead of print]328 118139

Esculin induces endoplasmic reticulum stress and drives apoptosis and ferroptosis in colorectal cancer via PERK regulating eIF2α/CHOP and Nrf2/HO-1 cascades.

Xiaoke Ji, Zongpin Chen, Weifan Lin, Qifang Wu, Yu Wu, Yan Hong, Haibin Tong, Changxiong Wang, Ya Zhang.

  ETHNOPHARMACOLOGICAL RELEVANCE: Cortex fraxini (also known as Qinpi), the bark of Fraxinus rhynchophylla Hance and Fraxinus stylosa Lingelsh, constitutes a crucial component in several traditional Chinese formulas (e.g., Baitouweng Tang, Jinxiao Formula, etc.) and has demonstrated efficacy in alleviating intestinal carbuncle and managing diarrhea. Cortex fraxini has demonstrated commendable anticancer activity in the realm of Chinese ethnopharmacology; nevertheless, the underlying mechanisms against colorectal cancer (CRC) remain elusive.AIM OF THE STUDY: Esculin, an essential bioactive compound derived from cortex fraxini, has recently garnered attention for its ability to impede viability and induce apoptosis in cancer cells. This investigation aims to assess the therapeutic potential of esculin in treating CRC and elucidate the underlying mechanisms.
MATERIALS AND METHODS: The impact of esculin on CRC cell viability was assessed using CCK-8 assay, Annexin V/PI staining, and Western blotting. Various cell death inhibitors, along with DCFH-DA, ELISA, biochemical analysis, and Western blotting, were employed to delineate the modes through which esculin induces HCT116 cells death. Inhibitors and siRNA knockdown were utilized to analyze the signaling pathways influenced by esculin. Additionally, an azomethane/dextran sulfate sodium (AOM/DSS)-induced in vivo CRC mouse model was employed to validate esculin's potential in inhibiting tumorigenesis and to elucidate its underlying mechanisms.
RESULTS: Esculin significantly suppressed the viability of various CRC cell lines, particularly HCT116 cells. Investigation with diverse cell death inhibitors revealed that esculin-induced cell death was associated with both apoptosis and ferroptosis. Furthermore, esculin treatment triggered cellular lipid peroxidation, as evidenced by elevated levels of malondialdehyde (MDA) and decreased levels of glutathione (GSH), indicative of its propensity to induce ferroptosis in HCT116 cells. Enhanced protein levels of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and p-eIF2α suggested that esculin induced cellular endoplasmic reticulum (ER) stress, subsequently activating the Nrf2/ARE signaling pathway and initiating the transcriptional expression of heme oxygenase (HO)-1. Esculin-induced excessive expression of HO-1 could potentially lead to iron overload in HCT116 cells. Knockdown of Ho-1 significantly attenuated esculin-induced ferroptosis, underscoring HO-1 as a critical mediator of esculin-induced ferroptosis in HCT116 cells. Furthermore, utilizing an AOM/DSS-induced colorectal cancer mouse model, we validated that esculin potentially inhibits the onset and progression of colon cancer by inducing apoptosis and ferroptosis in vivo.
CONCLUSIONS: These findings provide comprehensive insights into the dual induction of apoptosis and ferroptosis in HCT116 cells by esculin. The activation of the PERK signaling pathway, along with modulation of downstream eIF2α/CHOP and Nrf2/HO-1 cascades, underscores the mechanistic basis supporting the clinical application of esculin on CRC treatment.

Keywords:  Colorectal cancer; Esculin; Ferroptosis; Nrf2/HO-1; PERK

DOI:  https://doi.org/10.1016/j.jep.2024.118139
J Cancer. 2024 ;15(9): 2845-2865

Comprehensive analysis of IGF2BP3 with expression features, prognosis, immune modulation and stemness in hepatocellular carcinoma and pan-cancer.

Sha Qin, Haoer Jin, Yan Li, Xue Chen, Jiang He, Juxiong Xiao, Yan Qin, Chuyi Liu, Yitao Mao, Luqing Zhao.

  Insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) is a critical m6A reader. It encodes proteins that contain several KH domains, which are important in RNA binding, RNA synthesis and metabolism. Lots of researches have studied the malignant potential of m6A readers in tumors. However, the biological functional analysis of IGF2BP3 in hepatocellular carcinoma (HCC) and pan-cancer is not comprehensive. In this study, we used a bioinformatics approach to comprehensively analyze the significance of IGF2BP3 in HCC through analyzing its expression, mutation, prognosis, protein-protein interaction (PPI) network, functional enrichment, and the correlation with ferroptosis, stemness as well as immune modulation in HCC. IGF2BP3 presented a negative correlation with the ferroptosis molecule NFE2L2, and a positive correlation with the ferroptosis molecule SLC1A5 as well as the immune checkpoint HAVCR2. In addition, we also analyzed IGF2BP3 expression, prognosis and immune modulation in pan-cancer, revealing the prognostic value of IGF2BP3 in a variety of tumors. Finally, we verified the biological functions of IGF2BP3 in HCC through various experiments. The data showed that IGF2BP3 may enhance the proliferation, colony formation and invasion capacities of HCC cells, and IGF2BP3 is mainly positively correlated with the expression level of stemness marker SOX2. In conclusion, IGF2BP3 had a potential to be a new perspective biomarker in forecasting the immune response, ferroptosis, stemness and prognosis of HCC or even pan-cancer.

Keywords:  IGF2BP3; expression features; hepatocellular carcinoma (HCC); immune modulation; pan-cancer analysis.; prognosis

DOI:  https://doi.org/10.7150/jca.92768
Int Immunopharmacol. 2024 Mar 29. pii: S1567-5769(24)00477-6. [Epub ahead of print]132 111959

Ononin triggers ferroptosis-mediated disruption in the triple negative breast cancer both in vitro and in vivo.

Guowei Gong, Yukai Wan, Yaqun Liu, Zhenxia Zhang, Yuzhong Zheng.

  Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is difficult to treat due to a lack of targeted therapies. In this study, we aimed to investigate whether a natural flavonoid compound called ononin could be effective in treating TNBC by triggering ferroptosis in MDA-MB-231 and 4 T1 cell lines, and MDA-MB-231-xenograft nude mice model. Ononin inhibited TNBC through ferroptosis, which was determined by MTT assay, flow cytometry, RT-PCR, immunofluorescence, transmission electron microscopy, histological analysis, western blot and bioluminescence assay. Our results showed that treatment with ononin led to increased levels of malondialdehyde and reactive oxygen species and decreased activity of superoxide dismutase, which are indicatives of ferroptosis. We also found that ononin downregulated two key markers of ferroptosis, SLC7A11 and Nrf2, at both the transcriptional and translational level. Additionally, the administration of ononin resulted in a notable decrease in tumor size and weight in the mouse model. Furthermore, it was observed to enhance the rate of apoptosis in TNBC cells. Importantly, ononin did not induce any histological changes in the kidney, liver, and heart. Taken together, our findings suggest that ononin could be a promising therapeutic strategy for TNBC, and that it works by disrupting the Nrf2/SLC7A11 axis through ferroptosis. These results are encouraging and may lead to the development of new treatments for this challenging cancer subtype.

Keywords:  Ferroptosis; Nrf2/SLC7A11 axis; Ononin; Triple-negative breast cancer; Xenograft model

DOI:  https://doi.org/10.1016/j.intimp.2024.111959
Nat Commun. 2024 Mar 30. 15(1): 2803

Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies.

Saeed Daneshmandi, Jee Eun Choi, Qi Yan, Cameron R MacDonald, Manu Pandey, Mounika Goruganthu, Nathan Roberts, Prashant K Singh, Richard M Higashi, Andrew N Lane, Teresa W-M Fan, Jianmin Wang, Philip L McCarthy, Elizabeth A Repasky, Hemn Mohammadpour.

Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using β2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically.

DOI: https://doi.org/10.1038/s41467-024-47096-9
Free Radic Biol Med. 2024 Apr 01. pii: S0891-5849(24)00160-6. [Epub ahead of print]

Unlocking the anticancer activity of gambogic acid: a shift towards ferroptosis via a GSH/Trx dual antioxidant system.

Jinshuai Lan, Li Liu, Wenjun Zhao, Zhe Li, Ruifeng Zeng, Shiyuan Fang, Lixia Chen, Yi Shen, Hai Wei, Tong Zhang, Yue Ding.

  Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in ferroptosis by regulating the cellular antioxidant response and maintaining redox balance. However, compounds that induce ferroptosis through dual antioxidant pathways based on Nrf2 have not been fully explored. In our study, we investigated the impact of Gambogic acid (GA) on MCF-7 cells and HepG2 cells in vitro. The cytotoxicity, colony formation assay and cell cycle assay demonstrated potent tumor-killing ability of GA, while its effect was rescued by ferroptosis inhibitors. Furthermore, RNA sequencing revealed the enrichment of ferroptosis pathway mediated by GA. In terms of ferroptosis indicators detection, evidences for GA were provided including reactive oxygen species (ROS) accumulation, alteration in mitochondrial membrane potential (MMP), disappearance of mitochondrial cristae, lipid peroxidation induction, malondialdehyde (MDA) accumulation promotion, iron ion accumulation as well as glutathione (GSH)/thioredoxin (Trx) depletion. Notably, Ferrostatin-1 (Fer-1) and Liproxstatin-1 (Lip-1) successfully rescued GA-induced MDA accumulation. In terms of mechanism, Nrf2 was found to play a pivotal role in GA-induced ferroptosis by inducing protein alterations through the iron metabolism pathway and GSH/Trx dual antioxidant pathway. Furthermore, GA exerted good antitumor activity in vivo through GSH/Trx dual antioxidant pathway, and Fer-1 significantly attenuated its efficacy. In conclusion, our findings first provided new evidence for GA as an inducer of ferroptosis, and Nrf2-mediated GSH/Trx dual antioxidant system played an important role in GA-induced ferroptosis.

Keywords:  Ferroptosis; GSH; Gambogic acid; Nrf2; Thioredoxin

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.03.023
Sci Rep. 2024 Apr 03. 14(1): 7889

Nobiletin alleviates cisplatin-induced ototoxicity via activating autophagy and inhibiting NRF2/GPX4-mediated ferroptosis.

Wenao Song, Li Zhang, Xiaolin Cui, Rongrong Wang, Jingyu Ma, Yue Xu, Yan Jin, Dawei Wang, Zhiming Lu.

Nobiletin, a citrus polymethoxy flavonoid with antiapoptotic and antioxidative properties, could safeguard against cisplatin-induced nephrotoxicity and neurotoxicity. Cisplatin, as the pioneer of anti-cancer drug, the severe ototoxicity limits its clinical applications, while the effect of nobiletin on cisplatin-induced ototoxicity has not been identified. The current study investigated the alleviating effect of nobiletin on cisplatin-induced ototoxicity and the underlying mechanisms. Apoptosis and ROS formation were evaluated using the CCK-8 assay, Western blotting, and immunofluorescence, indicating that nobiletin attenuated cisplatin-induced apoptosis and oxidative stress. LC3B and SQSTM1/p62 were determined by Western blotting, qPCR, and immunofluorescence, indicating that nobiletin significantly activated autophagy. Nobiletin promoted the nuclear translocation of NRF2 and the transcription of its target genes, including Hmox1, Nqo1, and ferroptosis markers (Gpx4, Slc7a11, Fth, and Ftl), thereby inhibiting ferroptosis. Furthermore, RNA sequencing analysis verified that autophagy, ferroptosis, and the NRF2 signaling pathway served as crucial points for the protection of nobiletin against ototoxicity caused by cisplatin. Collectively, these results indicated, for the first time, that nobiletin alleviated cisplatin-elicited ototoxicity through suppressing apoptosis and oxidative stress, which were attributed to the activation of autophagy and the inhibition of NRF2/GPX4-mediated ferroptosis. Our study suggested that nobiletin could be a prospective agent for preventing cisplatin-induced hearing loss.

DOI: https://doi.org/10.1038/s41598-024-55614-4
Redox Rep. 2024 Dec;29(1): 2332038

Ivacaftor attenuates gentamicin-induced ototoxicity through the CFTR-Nrf2-HO1/NQO1 pathway.

Rui Hu, Fan Wu, Yi-Qing Zheng.

  OBJECTIVES: Gentamicin is one of the most common ototoxic drugs that can lower patients' quality of life. Oxidative stress is a key factors inducing sensory hair cell death during gentamicin administration. So far, there are no effective drugs to prevent or treat gentamicin- induced hearing loss. A recent study found cystic fibrosis transmembrane conductance regulator (CFTR) as a new target to modulate cellular oxidative balance. The objective of this study was to estimate the effect of the CFTR activator ivacaftor on gentamicin-induced ototoxicity and determine its mechanism.METHODS: The hair cell count was analyzed by Myosin 7a staining. Apoptosis was analyzed by TUNEL Apoptosis Kit. Cellular reactive oxygen species (ROS) level was detected by DCFH-DA probes. The Nrf2 related proteins expression levels were analyzed by western blot.
RESULTS: An in vitro cochlear explant model showed that gentamicin caused ROS accumulation in sensory hair cells and induced apoptosis, and this effect was alleviated by pretreatment with ivacaftor. Western blotting showed that ivacaftor administration markedly increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO1), and NAD(P)H:quinone oxidoreductase 1 (NQO1). The protective effect of ivacaftor was abolished by the Nrf2 inhibitor ML385.
DISCUSSION: Our results indicate the protective role of the CFTR-Nrf2-HO1/NQO1 pathway in gentamicin-induced ototoxicity. Ivacaftor may be repositioned or repurposed towards aminoglycosides-induced hearing loss.

Keywords:  Gentamicin, ototoxicity, sensory hair cells, CFTR, ivacaftor, Nrf2, oxidative stress, reactive oxygen species

DOI:  https://doi.org/10.1080/13510002.2024.2332038