bims-nurfca 2023-11-19 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2023–11–19
eight papers selected by
Caner Geyik, Istinye University

Regulation of NRF2 by Phosphoinositides and Small Heat Shock Proteins.
Evaluation of the therapeutic effects of arbutin on cisplatin-induced ovarian toxicity in rats through endoplasmic reticulum stress and Nrf2 pathway.
Heterogeneity of Phase II Enzyme Ligands on Controlling the Progression of Human Gastric Cancer Organoids as Stem Cell Therapy Model.
Down-Regulation of CYP3A4 by the KCa1.1 Inhibition Is Responsible for Overcoming Resistance to Doxorubicin in Cancer Spheroid Models.
Eicosapentaenoic acid enhances the sensitivity of osteosarcoma to cisplatin by inducing ferroptosis through the DNA-PKcs/AKT/NRF2 pathway and reducing PD-L1 expression to attenuate immune evasion.
Diallyl Disulfide Blocks Cigarette Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-Induced Lung Tumorigenesis via Activation of the Nrf2 Antioxidant System and Suppression of NF-κB Inflammatory Response.
Computational analysis of protein-protein interactions of cancer drivers in renal cell carcinoma.
Allyl isothiocyanate induces DNA damage and inhibits DNA repair-associated proteins in a human gastric cancer cells in vitro.

bioRxiv. 2023 Oct 27. pii: 2023.10.26.564194. [Epub ahead of print]

Regulation of NRF2 by Phosphoinositides and Small Heat Shock Proteins.

Changliang Chen, Mo Chen, Tianmu Wen, Richard A Anderson, Vincent L Cryns.

Reactive oxygen species (ROS) are generated by aerobic metabolism, and their deleterious effects are buffered by the cellular antioxidant response, which prevents oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of the antioxidant response. Basal levels of NRF2 are kept low by ubiquitin-dependent degradation of NRF2 by E3 ligases, including the Kelch-like ECH-associated protein 1 (KEAP1). Here, we show that the stability and function of NRF2 is regulated by the type I phosphatidylinositol phosphate kinase g (PIPKIg), which binds NRF2 and transfers its product phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ) to NRF2. PtdIns(4,5)P 2 binding recruits the small heat shock protein HSP27 to the complex. Silencing PIPKIg or HSP27 destabilizes NRF2, reduces expression of its target gene HO-1, and sensitizes cells to oxidative stress. These data demonstrate an unexpected role of phosphoinositides and HSP27 in regulating NRF2 and point to PIPKIg and HSP27 as drug targets to destabilize NRF2 in cancer.
In brief: Phosphoinositides are coupled to NRF2 by PIPKIγ, and HSP27 is recruited and stabilizes NRF2, promoting stress-resistance.

DOI: https://doi.org/10.1101/2023.10.26.564194
Reprod Biol. 2023 Nov 15. pii: S1642-431X(23)00096-7. [Epub ahead of print]23(4): 100824

Evaluation of the therapeutic effects of arbutin on cisplatin-induced ovarian toxicity in rats through endoplasmic reticulum stress and Nrf2 pathway.

Elif Ayazoglu Demir, Ahmet Mentese, Zeynep Sagnak Yilmaz, Nihal Turkmen Alemdar, Selim Demir, Yuksel Aliyazicioglu.

  Arbutin (ARB) is a glycosylated hydroquinone with potent antioxidant effects. Although cisplatin (CP) is widely used in chemotherapy, its toxicity in healthy tissues, including ovotoxicity, is an insurmountable problem. This study aimed to evaluate the therapeutic effect of ARB against CP-related ovototoxicity by including nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in rats for the first time. Rats treated one dose of CP (5 mg/kg) on the first day, followed by ARB (5 and 10 mg/kg) for three days. Serum reproductive hormone levels were determined using ELISA kits. Oxidative stress (OS), inflammation, endoplasmic reticulum stress (ERS) and apoptosis markers in ovarian tissue were also determined colorimetrically. In addition, how CP affects Nrf2 pathway and the effect of ARB on this situation were also addressed. ARB treatment reduced the levels of markers of OS, inflammation, ERS and apoptosis in ovarian tissue of CP-stimulated animals. ARB regenerated the depleted antioxidant system by triggering Nrf2 pathway in the ovarian tissues of animals stimulated by CP. Histological findings also supported the therapeutic efficacy of ARB. The results indicate that ARB may have therapeutic effects against CP-induced reproductive toxicity with its Nrf2 activator potential. ARB should be tested in more extensive studies as a new generation chemopreventive candidate molecule.

Keywords:  Arbutin; Cisplatin; Endoplasmic reticulum stress; Inflammation; Nrf2; Ovotoxicity; Oxidative stress

DOI:  https://doi.org/10.1016/j.repbio.2023.100824
Int J Mol Sci. 2023 Nov 02. pii: 15911. [Epub ahead of print]24(21):

Heterogeneity of Phase II Enzyme Ligands on Controlling the Progression of Human Gastric Cancer Organoids as Stem Cell Therapy Model.

Deng-Chyang Wu, Chia-Chen Ku, Jia-Bin Pan, Kenly Wuputra, Ya-Han Yang, Chung-Jung Liu, Yi-Chang Liu, Kohsuke Kato, Shigeo Saito, Ying-Chu Lin, Inn-Wen Chong, Michael Hsiao, Huang-Ming Hu, Chao-Hung Kuo, Kung-Kai Kuo, Chang-Shen Lin, Kazunari K Yokoyama.

  Gastric cancer (GC) organoids are frequently used to examine cell proliferation and death as well as cancer development. Invasion/migration assay, xenotransplantation, and reactive oxygen species (ROS) production were used to examine the effects of antioxidant drugs, including perillaldehyde (PEA), cinnamaldehyde (CA), and sulforaphane (SFN), on GC. PEA and CA repressed the proliferation of human GC organoids, whereas SFN enhanced it. Caspase 3 activities were also repressed on treatment with PEA and CA. Furthermore, the tumor formation and invasive activities were repressed on treatment with PEA and CA, whereas they were enhanced on treatment with SFN. These results in three-dimensional (3D)-GC organoids showed the different cancer development of phase II enzyme ligands in 2D-GC cells. ROS production and the expression of TP53, nuclear factor erythroid 2-related factor (NRF2), and Jun dimerization protein 2 were also downregulated on treatment with PEA and CA, but not SFN. NRF2 knockdown reversed the effects of these antioxidant drugs on the invasive activities of the 3D-GC organoids. Moreover, ROS production was also inhibited by treatment with PEA and CA, but not SFN. Thus, NRF2 plays a key role in the differential effects of these antioxidant drugs on cancer progression in 3D-GC organoids. PEA and CA can potentially be new antitumorigenic therapeutics for GC.

Keywords:  cinnamaldehyde; gastric cancer development; organoids; perillaldehyde; reactive oxygen species

DOI:  https://doi.org/10.3390/ijms242115911
Int J Mol Sci. 2023 Oct 27. pii: 15672. [Epub ahead of print]24(21):

Down-Regulation of CYP3A4 by the KCa1.1 Inhibition Is Responsible for Overcoming Resistance to Doxorubicin in Cancer Spheroid Models.

Susumu Ohya, Junko Kajikuri, Hiroaki Kito, Miki Matsui.

  The large-conductance Ca2+-activated K+ channel, KCa1.1, plays a pivotal role in cancer progression, metastasis, and the acquisition of chemoresistance. Previous studies indicated that the pharmacological inhibition of KCa1.1 overcame resistance to doxorubicin (DOX) by down-regulating multidrug resistance-associated proteins in the three-dimensional spheroid models of human prostate cancer LNCaP, osteosarcoma MG-63, and chondrosarcoma SW-1353 cells. Investigations have recently focused on the critical roles of intratumoral, drug-metabolizing cytochrome P450 enzymes (CYPs) in chemoresistance. In the present study, we examined the involvement of CYPs in the acquisition of DOX resistance and its overcoming by inhibiting KCa1.1 in cancer spheroid models. Among the CYP isoforms involved in DOX metabolism, CYP3A4 was up-regulated by spheroid formation and significantly suppressed by the inhibition of KCa1.1 through the transcriptional repression of CCAAT/enhancer-binding protein, CEBPB, which is a downstream transcription factor of the Nrf2 signaling pathway. DOX resistance was overcome by the siRNA-mediated inhibition of CYP3A4 and treatment with the potent CYP3A4 inhibitor, ketoconazole, in cancer spheroid models. The phosphorylation levels of Akt were significantly reduced by inhibiting KCa1.1 in cancer spheroid models, and KCa1.1-induced down-regulation of CYP3A4 was reversed by the treatment with Akt and Nrf2 activators. Collectively, the present results indicate that the up-regulation of CYP3A4 is responsible for the acquisition of DOX resistance in cancer spheroid models, and the inhibition of KCa1.1 overcame DOX resistance by repressing CYP3A4 transcription mainly through the Akt-Nrf2-CEBPB axis.

Keywords:  Akt-Nrf2; CYP3A4; Ca2+-activated K+ channel; KCa1.1; cancer spheroid; doxorubicin resistance

DOI:  https://doi.org/10.3390/ijms242115672
Int Immunopharmacol. 2023 Nov 09. pii: S1567-5769(23)01507-2. [Epub ahead of print]125(Pt B): 111181

Eicosapentaenoic acid enhances the sensitivity of osteosarcoma to cisplatin by inducing ferroptosis through the DNA-PKcs/AKT/NRF2 pathway and reducing PD-L1 expression to attenuate immune evasion.

Yining Zhang, Guohong Shen, Tingting Meng, Zhaorui Lv, Xin Li, Jianmin Li, Ka Li.

  Acquired drug resistance poses a significant challenge in osteosarcoma therapy. Therefore, it is necessary for us to discover and develop an alternative anti-cancer strategy. Previous studies have shown that eicosapentaenoic acid (EPA) significantly increases chemosensitivity in cancer cells. In this study, we discovered that EPA enhances the sensitivity of osteosarcoma to cisplatin (DDP). Interestingly, in addition to inhibiting growth and inducing apoptosis, EPA also enhances DDP-induced ferroptosis. Western blot analysis confirmed that EPA treatment significantly decreases the expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), p-AKT, nuclear factor erythroid 2-related factor 2 (NRF2), and glutathione peroxidase 4 (GPX4) in cells. Knockdown of DNA-PKcs by siRNA further enhances the level of ferroptosis induced by EPA. Importantly, EPA can reverse the high expression level of programmed death ligand 1 (PD-L1) induced by DDP. ELISA and western blotting analysis revealed that EPA treatment decreases the levels of IL-6 and p-STAT3, which are increased by DDP treatment. Furthermore, a co-immunoprecipitation (co-IP) assay confirmed the interaction between DNA-PKcs and PD-L1, and knockdown of DNA-PKcs further reduces the expression of PD-L1. This data provides the first evidence that EPA suppresses the DNA-PKcs/AKT/NRF2/GPX4 pathway to enhance ferroptosis, and inhibits IL-6/STAT3 and DNA-PKcs to decrease PD-L1 expression, thereby sensitizing osteosarcoma to DDP. The combination of EPA and DDP presents an encouraging and promising anti-tumor strategy.

Keywords:  DDP; EPA; Ferroptosis; Osteosarcoma; PD-L1

DOI:  https://doi.org/10.1016/j.intimp.2023.111181
J Agric Food Chem. 2023 Nov 13.

Diallyl Disulfide Blocks Cigarette Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-Induced Lung Tumorigenesis via Activation of the Nrf2 Antioxidant System and Suppression of NF-κB Inflammatory Response.

Jiahui Tian, Wenli Zhao, Yanran Wu, Ying Shi, Jianqiang Yu, Wannian Zhang, Chengguo Xing, Chunlin Zhuang, Zhuo Qu.

  Chemoprevention is a potential strategy to reduce lung cancer incidence and death. Recently, we reported that garlic oil significantly inhibits 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis. Diallyl disulfide (DADS) is a bioactive ingredient in garlic. Our goal was to examine the chemopreventive effectiveness and mechanism of DADS on NNK-triggered lung cancer in vivo and in vitro in the current investigation. The results indicated that DADS significantly reduced the number of lung nodules in the NNK-induced A/J mice. Consistent with the in vivo results, DADS markedly inhibited NNK-induced decrease of MRC-5 cells' viability. Mechanistically, DADS could promote Nrf2 dissociated from the Keap1-Nrf2 complex and accelerate Nrf2 nuclear translocation, which in turn upregulates its downstream target genes. Besides, DADS further inhibited the NF-κB signaling cascade, thus reducing the accumulation of inflammatory factors. Collectively, these discoveries supported the potential of DADS as a novel candidate for the chemoprevention of tobacco-carcinogen-induced lung cancer.

Keywords:  NF-κB; NNK; Nrf2 signaling pathway; chemoprevention; diallyl disulfide; lung cancer

DOI:  https://doi.org/10.1021/acs.jafc.3c02007
FEBS Open Bio. 2023 Nov 14.

Computational analysis of protein-protein interactions of cancer drivers in renal cell carcinoma.

Jimin Pei, Jing Zhang, Qian Cong.

  Renal cell carcinoma (RCC) is the most common type of kidney cancer with rising cases in recent years. Extensive research has identified various cancer-driver proteins associated with different subtypes of RCC. Most RCC drivers are encoded by tumor suppressor genes and exhibit enrichment in functional categories such as protein degradation, chromatin remodeling, and transcription. To further our understanding of RCC, we utilized powerful deep learning methods based on AlphaFold to predict protein-protein interactions (PPIs) involving RCC drivers. We predicted high-confidence complexes formed by various RCC drivers, including TCEB1, KMT2C/D, and KDM6A of the COMPASS-related complexes, TSC1 of the MTOR pathway, and TRRAP. These predictions provide valuable structural insights into the interaction interfaces, some of which are promising targets for cancer drug design, such as the NRF2-MAFK interface. Cancer somatic missense mutations from large datasets of genome sequencing of RCCs were mapped to the interfaces of predicted and experimental structures of PPIs involving RCC drivers, and their effects on the binding affinity were evaluated. We observed more than 100 cancer somatic mutations affecting the binding affinity of complexes formed by key RCC drivers such as VHL and TCEB1. These findings emphasize the importance of these mutations in RCC pathogenesis and potentially offer new avenues for targeted therapies.

Keywords:  cancer drivers; chromatin remodeling; protein-protein interaction; renal cell carcinoma; ubiquitination

DOI:  https://doi.org/10.1002/2211-5463.13732
Environ Toxicol. 2023 Nov 15.

Allyl isothiocyanate induces DNA damage and inhibits DNA repair-associated proteins in a human gastric cancer cells in vitro.

Yung-Luen Shih, Sheng-Yao Hsu, Kuang-Chi Lai, Fu-Shin Chueh, Yuan-Li Huang, Chao-Lin Kuo, Yung-Liang Chen, Chiung-Ju Chen, Shu-Fen Peng, Wen-Wen Huang, Hsu-Fen Lu.

  Allyl isothiocyanate (AITC) is abundant in cruciferous vegetables and it present pharmacological activity including anticancer activity in many types of human cancer cells in vitro and in vivo. Currently, no available information to show AITC affecting DNA damage and repair-associated protein expression in human gastric cancer cells. Therefore, in the present studies, we investigated AITC-induced cytotoxic effects on human gastric cancer in AGS and SNU-1 cells whether or not via the induction of DNA damage and affected DNA damage and repair associated poteins expressions in vitro. Cell viability and morphological changes were assayed by flow cytometer and phase contrast microscopy, respectively, the results indicated AITC induced cell morphological changes and decreased total viable cells in AGS and SNU-1 cells in a dose-dependently. AITC induced DNA condensation and damage in a dose-dependently which based on the cell nuclei was stained by 4', 6-diamidino-2-phenylindole present in AGS and SNU-1 cells. DNA damage and repair associated proteins expression in AGS and SNU-1 cells were measured by Western blotting. The results indicated AITC decreased nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), glutathione, and catalase, but increased superoxide dismutase (SOD (Cu/Zn)), and nitric oxide synthase (iNOS) in AGS cells, however, in SNU-1 cells are increased HO-1. AITC increased DNA-dependent protein kinase (DNA-PK), phosphorylation of gamma H2A histone family member X on Ser139 (γH2AXpSer139 ), and heat shock protein 90 (HSP90) in AGS cells. AITC increased DNA-PK, mediator of DNA damage checkpoint protein 1 (MDC1), γH2AXpSer139 , topoisomerase II alpha (TOPIIα), topoisomerase II beta (TOPIIβ), HSP90, and heat shock protein 70 (HSP70) in SNU-1 cells. AITC increased p53, p53pSer15 , and p21 but decreased murine double minute 2 (MDM2)pSer166 and O6 -methylguanine-DNA methyltransferase (MGMT) in AGS cells; however, it has a similar effect of AITC except increased ataxia telangiectasia and Rad3 -related protein (ATR)pSer428 , checkpoint kinase 1 (CHK1), and checkpoint kinase 2 (CHK2) in SNU-1 cells. Apparently, both cell responses to AITC are different, nonetheless, all of these observations suggest that AITC inhibits the growth of gastric cancer cells may through induction off DNA damage in vitro.

Keywords:  AITC; DNA damage; DNA repair; allyl isothiocyanate; gastric cancer

DOI:  https://doi.org/10.1002/tox.24020