Interaction of Nrf2 with dimeric STAT3 induces IL-23 expression: Implications for breast cancer progression

Kim, Su Jung; Saeidi, Soma; Cho, Nam Chul; Kim, Seung Hyeon; Lee, Han‐Byoel; Han, Wonshik; Noh, Dong Young; Surh, Young Joon

doi:10.1016/j.canlet.2020.11.047

Cited by 19 publications

(14 citation statements)

References 80 publications

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“…The nuclear factor erythroid 2-related factor 2 (Nrf2) is an endogenous antioxidant signaling involved in the regulation of antioxidantoxidative stress balance. The Nrf2 induces the transcription of genes such as HO-1 via antioxidant response element protein [8,9]. Similarly, these inflammatory mediators induce the activation of several inflammatory pathways such as NF-κB, which plays crucial role in the transformation of chronic inflammation to tumor formation [10].…”

Section: Introductionmentioning

confidence: 99%

N‐(benzylidene)‐2‐((2‐hydroxynaphthalen‐1‐yl)diazenyl)benzohydrazides (1‐2) (NCHDH and NTHDH) attenuate DMBA‐induced breast cancer via Nrf2/NF‐κB/apoptosis signaling

Khan

Shal

et al. 2022

Fundamemntal Clinical Pharma

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The present study investigated the effect of the N-(benzylidene)-2-((2-hydroxynaphthalen-1-yl)diazenyl)benzohydrazides (1-2) (NCHDH and NTHDH) against breast cancer using in vitro and in vivo approaches. The NCHDH and NTHDH significantly inhibited the growth of the MCF-7 cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The NCHDH and NTHDH treatment significantly inhibited the tumor size, tumor weight, and tumor volume, while it enhanced the survival and tumor free survival rate following 7,12-Dimethylbenz[a]anthracene (DMBA)induced breast cancer. The NCHDH and NTHDH markedly attenuated the oxidative stress markers and induced the antioxidant level. The enzymelinked immunosorbent assay (ELISA) showed significant reduction in the inflammatory cytokines production compared with the DMBA control. The NCHDH and NTHDH treatment significantly improved the histological features using hematoxylin and eosin (H and E) staining, Masson's trichrome, PAS (periodic acid Schiff), and Toluidine blue staining compared with the DMBA-induced group. The NCHDH and NTHDH treatment improved the hematological and serological parameters following DMBA-induced breast tumor compared with DMBA-induced group. Furthermore, the NCHDH and NTHDH treatment significantly enhanced the antioxidants signaling proteins such as nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme oxygenase 1 (HO-1). The NCHDH and NTHDH enhanced the inhibitor of NF-κB (IκB) level, while it attenuated the NF-κB level. Similarly, the NCHDH and NTHDH showed marked increase in the apoptosis proteins such as Caspase-3, Caspase-9, and Bcl-2 Associated X-protein (Bax), while it inhibited the B-cell lymphoma 2 (Bcl-2) expression. In conclusion, the NCHDH and NTHDH significantly improved the DMBA-induced breast cancer via attenuating oxidative stress and inflammatory cytokines.

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Section: Introductionmentioning

confidence: 99%

N‐(benzylidene)‐2‐((2‐hydroxynaphthalen‐1‐yl)diazenyl)benzohydrazides (1‐2) (NCHDH and NTHDH) attenuate DMBA‐induced breast cancer via Nrf2/NF‐κB/apoptosis signaling

Khan

Shal

et al. 2022

Fundamemntal Clinical Pharma

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“…Furthermore, 15-keto-PGE 2 interacts directly with Cys251 and Cys259 [ 59 ]. Notably, mutation of STAT3 Cys259 significantly retarded the growth of PC-3 prostate cancer cells, which resembles an effect achieved by covalent modification of the same amino acid by 15d-PGJ 2 [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

STAT3 as a Potential Target for Tumor Suppressive Effects of 15-Deoxy-δ^12,14-prostaglandin J₂ in Triple Negative Breast Cancer

et al. 2021

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STAT3 plays a prominent role in proliferation and survival of tumor cells. Thus, STAT3 has been considered to be a prime target for development of anti-cancer therapeutics. The electrophilic cyclopentenone prostaglandin,15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) has been well recognized for its capability to modulate intracellular signaling pathways involved in cancer cell growth and progression. We previously reported that 15d-PGJ 2 had potent cytotoxicity against harvey-ras transformed human mammary epithelial cells through direct interaction with STAT3. In this study, we have attempted to verify the inhibitory effects of 15d-PGJ 2 on STAT3 signaling in human breast tumor cells. The triple negative breast cancer cell lines, MDA-MB-231 and MDA-MB-468 displaying constitutive phosphorylation of STAT3 on the tyrosine 705 (Tyr705) residue, underwent apoptosis upon inhibition of STAT3 by 15d-PGJ 2 . In contrast, estrogen receptor positive MCF-7 breast cancer cells that do not exhibit elevated STAT3 phosphorylation were much less susceptible to 15d-PGJ 2 -induced apoptosis as assessed by PARP cleavage. Furthermore, 15d-PGJ 2 inhibited interleukin-6-induced tyrosine phosphorylation of STAT3 in LNCaP cells. According to molecular docking studies, 15d-PGJ 2 may preferentially bind to the cysteine 259 residue (Cys259) present in the coiled-coil domain of STAT3. Site-directed mutagenesis of STAT3 identified Cys259 to be the critical amino acid for the 15d-PGJ 2 -induced apoptosis as well as epithelial-to-mesenchymal transition. Taken together, these findings suggest STAT3 inactivation through direct chemical modification of its Cys259 as a potential therapeutic approach for treatment of triple negative breast cancer treatment.

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“…Pearson correlation coefficient was used to predict the relationship between two genes. Gene set enrichment analysis (GSEA) for FGFR1 expression in primary breast cancer samples was performed as described previously [ 15 ]. The Kaplan–Meier plotter, an online biomarker validation tool (kmplot.com/analysis), was used to estimate survival probabilities for 255 triple negative breast cancer (TNBC) patients based on FGFR1 and Nrf2 gene expression.…”

Section: Methodsmentioning

confidence: 99%

Nuclear Localization of Fibroblast Growth Factor Receptor 1 in Breast Cancer Cells Interacting with Cancer Associated Fibroblasts

Suh

Kim

et al. 2022

J Cancer Prev

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Cancer-associated fibroblasts (CAFs) represent a major component of the tumor microenvironment and interplay with cancer cells by secreting cytokines, growth factors and extracellular matrix proteins. When estrogen receptor-negative breast cancer MDA-MB-231 cells were treated with the CAF-conditioned medium (CAF-CM), Akt and STAT3 involved in cell proliferation and survival were activated through phosphorylation. CAFs secrete fibroblast growth factor 2 (FGF2), thereby stimulating breast cancer cell progression. Akt activation induced by CAF-CM in MDA-MB-231 cells was abolished when FGF2-neutralizing antibody was added. Treatment of MDA-MB-231 cells directly with FGF2 enhanced the phosphorylation of Akt and the FGF receptor (FGFR) substrate, FRS2α. These events were abrogated by siRNA-mediated silencing of FGFR1. In a xenograft mouse model, co-injection of MDA-MB-231 cells with activated fibroblasts expressing FGF2 dramatically enhanced activation of Akt. Stable knockdown of FGFR1 blunted Akt phosphorylation in xenograft tumors. MDA-MB-231 cells co-cultured with CAFs or directly stimulated with FGF2 exhibited enhanced nuclear localization of FGFR1. Notably, FGF2 stimulation produced reactive oxygen species (ROS) accumulation in MDA-MB-231 cells, and FGF2-induced nuclear accumulation of FGFR1 was abrogated by the ROS scavenging agent, N -acetylcysteine.

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Interaction of Nrf2 with dimeric STAT3 induces IL-23 expression: Implications for breast cancer progression

Cited by 19 publications

References 80 publications

N‐(benzylidene)‐2‐((2‐hydroxynaphthalen‐1‐yl)diazenyl)benzohydrazides (1‐2) (NCHDH and NTHDH) attenuate DMBA‐induced breast cancer via Nrf2/NF‐κB/apoptosis signaling

N‐(benzylidene)‐2‐((2‐hydroxynaphthalen‐1‐yl)diazenyl)benzohydrazides (1‐2) (NCHDH and NTHDH) attenuate DMBA‐induced breast cancer via Nrf2/NF‐κB/apoptosis signaling

STAT3 as a Potential Target for Tumor Suppressive Effects of 15-Deoxy-δ^12,14-prostaglandin J₂ in Triple Negative Breast Cancer

Nuclear Localization of Fibroblast Growth Factor Receptor 1 in Breast Cancer Cells Interacting with Cancer Associated Fibroblasts

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Interaction of Nrf2 with dimeric STAT3 induces IL-23 expression: Implications for breast cancer progression

Cited by 19 publications

References 80 publications

N‐(benzylidene)‐2‐((2‐hydroxynaphthalen‐1‐yl)diazenyl)benzohydrazides (1‐2) (NCHDH and NTHDH) attenuate DMBA‐induced breast cancer via Nrf2/NF‐κB/apoptosis signaling

N‐(benzylidene)‐2‐((2‐hydroxynaphthalen‐1‐yl)diazenyl)benzohydrazides (1‐2) (NCHDH and NTHDH) attenuate DMBA‐induced breast cancer via Nrf2/NF‐κB/apoptosis signaling

STAT3 as a Potential Target for Tumor Suppressive Effects of 15-Deoxy-δ12,14-prostaglandin J2 in Triple Negative Breast Cancer

Nuclear Localization of Fibroblast Growth Factor Receptor 1 in Breast Cancer Cells Interacting with Cancer Associated Fibroblasts

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STAT3 as a Potential Target for Tumor Suppressive Effects of 15-Deoxy-δ^12,14-prostaglandin J₂ in Triple Negative Breast Cancer