bims-nurfca 2024-06-16 papers

Issue of 2024‒06‒16
six papers selected by
Caner Geyik, Istinye University

Free Radic Biol Med. 2024 Jun 12. pii: S0891-5849(24)00525-2. [Epub ahead of print]

A comparative analysis indicates SLC7A11 expression regulate the prognostic value of KEAP1-NFE2L2-CUL3 mutations in human Uterine Corpus Endometrial Carcinoma.

Akhileshwar Namani, Durga Devi Veeraiyan, Tapas Patra.

Uterine corpus endometrial cancer (UCEC) is a third most common malignancy in women with a poor prognosis in advanced stages. In this study, we performed an integrated comparative analysis of exome and transcriptome data from The Cancer Genome Atlas (TCGA), Lung Adenocarcinoma (LUAD), and UCEC patients. Our multi-omics analysis shows that the UCEC patients carrying mutations in the KEAP1-NFE2L2-CUL3 genes were associated with better progression-free survival, whereas the KEAP1-NFE2L2-CUL3 mutation in LUAD showed poor outcomes. Functional annotations and correlative expression studies show that genes, particularly GCLC and GCLM related to glutathione synthesis are expressed at lower levels in the KEAP1-NFE2L2-CUL3 mutant UCEC compared to LUAD and result in glutathione deficiency to combat intracellular reactive oxygen species (ROS). However, the expression of genes involved in the glutathione recycling process was not affected. On the other hand, cellular import of cystine is high due to increased SLC7A11 expression in UCEC. Because glutathione synthesis is impaired, the unconverted cysteine accumulates in cells, leading to di-sulfite stress. Apart from NRF2, ARID1A is one of the positive regulators of SLC7A11. In support, UCEC patients with co-occurrence of KEAP1-NFE2L2-CUL3 and ARID1A mutation shows significantly decreased PFS with decline of SLC7A11 expression as compared to patients carrying only KEAP1-NFE2L2-CUL3 mutation. Thus, we hypothesize that the KEAP1-NFE2L2-CUL3 mutation in UCEC leads to uncontrollable ROS with di-sulfite stress, reflecting a favorable clinical outcome.

Keywords: Glutathione synthesis; KEAP1-NFE2L2-CUL3 mutation; Progression free survival; The cancer genome atlas; Uterine corpus endometrial carcinoma

DOI: https://doi.org/10.1016/j.freeradbiomed.2024.06.008

Mol Biol Rep. 2024 Jun 12. 51(1): 729

Metformin-induced oxidative stress inhibits LNCaP prostate cancer cell survival.

Sashana Dixon, Alice Tran, Matthew S Schrier, Jianan Dong, Richard C Deth, Ana Castejon, Malav S Trivedi.

BACKGROUND: Preclinical and clinical studies over the past several decades have indicated the potential value of metformin, a widely utilized treatment for Type 2 diabetes, in prostate cancer therapy. Notably, these studies demonstrated metformin's pleiotropic effects on several molecular and metabolic pathways, such as androgen signaling, cell cycle, and cellular bioenergetics. In this study we investigated the role of metformin in regulating intracellular redox status and cell survival in LNCaP prostate cancer cells.METHODS AND RESULTS: The cytotoxic effects of metformin with or without the presence of SBI0206965 (AMPK inhibitor) on LNCaP cells were determined using MTT and trypan blue exclusion assays. Seahorse XP extracellular analysis, Liquid Chromatography/ Mass Spectrophotometry (LC/MS), and 2,7- and Dichlorofluoresin diacetate (DCFDA) assay were used to assess the effects of metformin on cellular bioenergetics, redox status, and redox-related metabolites. mRNA expression and protein concentration of redox-related enzymes were measured using Real Time-qPCR and ELISA assay, respectively. Independently of AMP-activated protein kinase, metformin exhibited a dose- and time-dependent inhibition of LNCaP cell survival, a response mitigated by glutathione or N-acetylcysteine (ROS scavengers) treatment. Notably, these findings were concomitant with a decline in ATP levels and the inhibition of oxidative phosphorylation. The results further indicated metformin's induction of reactive oxygen species, which significantly decreased glutathione levels and the ratio of reduced to oxidized glutathione, as well as the transsulfuration metabolite, cystathionine. Consistent with an induction of oxidative stress condition, metformin increased mRNA levels of the master redox transcription factor Nrf-2 (nuclear factor erythroid-derived 2-like), as well as transsulfuration enzymes cystathionine beta-synthase and cystathionase and GSH synthesis enzymes γ-glutamylcysteine synthetase and glutathione synthetase.
CONCLUSION: Our findings highlight multiple mechanisms by which metformin-induced formation of reactive oxygen species may contribute to its efficacy in prostate cancer treatment, including promotion of oxidative stress, Nrf2 activation, and modulation of redox-related pathways, leading to its anti-survival action.

Keywords: Bioenergetics; Glutathione; Metformin; Oxidative stress; Prostate cancer; Redox; Transsulfuration pathway

DOI: https://doi.org/10.1007/s11033-024-09662-8

Chem Biol Drug Des. 2024 Jun;103(6): e14565

Brusatol induces ferroptosis to inhibit hepatocellular carcinoma progression by targeting ATF3.

Yuanyuan Wan, Jingsong Cheng, Debiao Gan, Jiaming He, An Chen, Jing Ma, Yunying Li, Xiao Wang, Jianhua Ran, Dilong Chen, Jing Li.

Ferroptosis is a novel form of programmed cell death that is triggered by iron-dependent lipid peroxidation. Brusatol (BRU), a natural nuclear factor erythroid 2-related factor 2 inhibitor, exhibits potent anticancer effects in various types of cancer. However, the exact mechanism of BRU in the treatment of hepatocellular carcinoma (HCC) remains unknown. The anticancer effects of BRU in HCC were detected using cell counting kit-8 and colony formation assays and a xenograft model. RNA sequencing (RNA-seq) and bioinformatics analyses of HCC cells were utilized to elucidate the mechanism underlying the effects of BRU in HCC. The levels of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and Fe2+ were measured using assay kits. The expression of activating transcription factor 3 (ATF3) was tested using RT-qPCR, western blotting, and immunofluorescence staining. The role of ATF3 in BRU-induced ferroptosis was examined using siATF3. BRU significantly inhibited HCC cell proliferation, both in vitro and in vivo. BRU activated the ferroptosis signaling pathway and increased ATF3 expression. Furthermore, ATF3 knockdown impeded BRU-induced ferroptosis. BRU suppressed HCC growth through ATF3-mediated ferroptosis, supporting BRU as a promising therapeutic agent for HCC.

Keywords: ATF3; bioinformatics; brusatol; ferroptosis; hepatocellular carcinoma

DOI: https://doi.org/10.1111/cbdd.14565

Nat Metab. 2024 Jun 14.

Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer.

Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine-glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT). LKB1 loss, in collaboration with KEAP1 loss, activated SHMT through inactivation of the salt-induced kinase (SIK)-NRF2 axis and satisfied the increased demand for one-carbon units necessary for antioxidant defence. Chemical and genetic SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor enhanced the in vivo therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing oxidative stress) in KEAP1-mutant KL tumours. The data reveal how this highly aggressive molecular subtype of NSCLC fulfills their metabolic requirements and provides insight into therapeutic strategies.

DOI: https://doi.org/10.1038/s42255-024-01066-z

Redox Rep. 2024 Dec;29(1): 2365590

Evaluating anticancer activity of emodin by enhancing antioxidant activities and affecting PKC/ADAMTS4 pathway in thioacetamide-induced hepatocellular carcinoma in rats.

Hanan M Hassan, Ahmed M Hamdan, Abdullah Alattar, Reem Alshaman, Omar Bahattab, Mohammed M H Al-Gayyar.

Emodin is a naturally occurring anthraquinone derivative with a wide range of pharmacological activities, including neuroprotective and anti-inflammatory activities. We aim to assess the anticancer activity of emodin against hepatocellular carcinoma (HCC) in rat models using the proliferation, invasion, and angiogenesis biomarkers. After induction of HCC, assessment of the liver impairment and the histopathology of liver sections were investigated. Hepatic expression of both mRNA and protein of the oxidative stress biomarkers, HO-1, Nrf2; the mitogenic activation biomarkers, ERK5, PKCδ; the tissue destruction biomarker, ADAMTS4; the tissue homeostasis biomarker, aggregan; the cellular fibrinolytic biomarker, MMP3; and of the cellular angiogenesis biomarker, VEGF were measured. Emodin increased the survival percentage and reduced the number of hepatic nodules compared to the HCC group. Besides, emodin reduced the elevated expression of both mRNA and proteins of all PKC, ERK5, ADAMTS4, MMP3, and VEGF compared with the HCC group. On the other hand, emodin increased the expression of mRNA and proteins of Nrf2, HO-1, and aggrecan compared with the HCC group. Therefore, emodin is a promising anticancer agent against HCC preventing the cancer prognosis and infiltration. It works through many mechanisms of action, such as blocking oxidative stress, proliferation, invasion, and angiogenesis.

Keywords: ADAMTS4; Aggrecan; Angiogenesis; ERK5; HO-1; MMP3; Nrf2; PKCδ; VEGF; emodin; hepatocellular carcinoma

DOI: https://doi.org/10.1080/13510002.2024.2365590

Biomed Pharmacother. 2024 Jun 07. pii: S0753-3322(24)00716-9. [Epub ahead of print]176 116832

Berberine synergises with ferroptosis inducer sensitizing NSCLC to ferroptosis in p53-dependent SLC7A11-GPX4 pathway.

Weilin Liao, Ren Zhang, Geer Chen, Xiaoyu Zhu, Weiyu Wu, Ziyu Chen, Chenyu Jiang, Zicong Lin, Lijuan Ma, Haijie Yu.

Berberine (BBR) is a compound derived from Chinese herbal medicine, known for its anticancer properties through multiple signaling pathways. However, whether BBR can inhibit tumor growth by participating in ferroptosis remains unconfirmed. In this study, we demonstrated that berberine synergistically inhibited NSCLC in combination with multiple ferroptosis inducers, and this combination synergistically down-regulated the mRNA and protein expression of SLC7A11, GPX4, and NRF2, resulting in ferroptosis accompanied by significant depletion of GSH, and aberrant accumulation of reactive oxygen species and malondialdehyde. In a lung cancer allograft model, the combination treatment exhibited enhanced anticancer effects compared to using either drug alone. Notably, p53 is critical in determining the ferroptosis sensitivity. We found that the combination treatment did not elicit a synergistic anticancer effect in cells with a p53 mutation or with exogenous expression of mutant p53. These findings provide insight into the mechanism by which combination induces ferroptosis and the regulatory role of p53 in this process. It may guide the development of new strategies for treating NSCLC, offering great medical potential for personal diagnosis and treatment.

Keywords: Berberine; NSCLC; ferroptosis; p53; sulfasalazine

DOI: https://doi.org/10.1016/j.biopha.2024.116832