bims-nurfca 2023-09-10 papers

Issue of 2023–09–10
four papers selected by
Caner Geyik, Istinye University

PLoS One. 2023 ;18(9): e0290264

Thymidylate synthase promotes esophageal squamous cell carcinoma growth by relieving oxidative stress through activating nuclear factor erythroid 2-related factor 2 expression.

Jian Yang, Jingjing Zhang, Jingtian Chen, Xiaolong Yang, Hui Sun, Zhenxiang Zhao, Hui Zhou, Hao Shen.

BACKGROUND: Thymidylate synthase (TYMS) is involved in the malignant process of multiple cancers, and has gained much attention as a cancer treatment target. However, the mechanism in carcinogenesis of esophageal squamous cell cancer (ESCC) is little reported. The present study was to clear the biological roles and carcinogenic mechanism of TYMS in ESCC, and explored the possibility to use TYMS as a tumor marker in diagnosis and a drug target for the treatment of ESCC.
METHODS: Stably TYMS-overexpression cells established by lentivirus transduction were used for the analysis of cell proliferation. RNA sequencing was performed to explore the possible carcinogenic mechanisms.
RESULTS: GEPIA databases analysis showed that TYMS expression in esophageal cancer tissues was higher than that in normal tissues. The MTT assay, colony formation assay, and nude mouse subcutaneous tumor model found that the overexpression of TYMS increased cell proliferation. Transcriptome sequencing analysis revealed that the promoted cell proliferation in TYMS-overexpression ESCC cells were mediated through activating genes expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2 dependent antioxidant enzymes to relieve oxidative stress, which was confirmed by increased glutathione (GSH), glutathione peroxidase (GPX) activities, and reduced reactive oxygen species. Nrf2 active inhibitors (ML385) used in TYMS-overexpression cells inhibited the expression of Nrf2-dependent antioxidant enzyme genes, thereby increasing oxidative stress and blocking cell proliferation.
CONCLUSION: Our study indicated a novel and effective regulatory capacity of TYMS in the cell proliferation of ESCC by relieving oxidative stress through activating expression of Nrf2 and Nrf2-dependent antioxidant enzymes genes. These properties make TYMS and Nrf2 as appealing targets for ESCC clinical chemotherapy.

DOI: https://doi.org/10.1371/journal.pone.0290264

J Biol Chem. 2023 Sep 01. pii: S0021-9258(23)02243-3. [Epub ahead of print] 105215

SUMOylation of the ubiquitin ligase component KEAP1 at K39 upregulates NRF2 and its target function in lung cancer cells proliferation.

Hao Yang, Yuzhang Du, Xuefeng Fei, Shu Huang, Maimaitiaili Yimiti, Xiaobao Yang, Junrui Ma, Shuhui Li, Huxidanmu Tuoheniyazi, Yanan Zhao, Zhidong Gu, Dakang Xu.

Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) is important for the expression of genes associated with oxidative stress. The levels of NRF2 are controlled by Kelch-like ECH-associated protein 1 (KEAP1) -dependent degradation. Although oxidative stress is known to suppress KEAP1 activity to stabilize the levels of NRF2, the mechanism for this control is unclear. Here, we identify that KEAP1 is modified by SUMO1 at the lysine residue position 39 (K39). Arginine replacement of this lysine (K39R) in KEAP1 did not affect its stability, subcellular localization or dimerization but promoted the formation of the Cullin 3 ubiquitin ligase and increased NRF2 ubiquitination. This was accompanied by decreased NRF2 expression. Gene reporter assays showed that the transcription of antioxidant response elements was heightened in KEAP1-WT cells compared to cells expressing the KEAP1-K39R SUMO1 substrate mutant. Consistent with this, chromatin immunoprecipitation assays revealed higher NRF2 binding to the promoter regions of antioxidant genes in cells expressing the KEAP1-WT compared to the KEAP1-K39R mutant protein in H1299 lung cancer cell. The significance of this suppression of KEAP1 activity by its SUMOylation was tested in a subcutaneous tumor model of H1299 lung cancer cell lines that differentially expressed the WT and K39R KEAP1 constructs. This model showed that mutating the SUMOylation site on KEAP1 altered the production of reactive oxygen species and suppressed tumor growth. Taken together, our study recognizes that NRF2-dependent redox control is regulated by the SUMOylation of KEAP1. These findings identify a potential new therapeutic option to counteract oxidative stress.

Keywords: KEAP1; NRF2; SUMOylation; cell proliferation; oxidative stress

DOI: https://doi.org/10.1016/j.jbc.2023.105215

Dig Liver Dis. 2023 Sep 04. pii: S1590-8658(23)00907-6. [Epub ahead of print]

Nrf2 in cancer: An insufficiently explored and controversial research area.

Zheng Yang.

DOI: https://doi.org/10.1016/j.dld.2023.08.056

Cells. 2023 Sep 01. pii: 2190. [Epub ahead of print]12(17):

Attenuation of Oxidative Damage via Upregulating Nrf2/HO-1 Signaling Pathway by Protease SH21 with Exerting Anti-Inflammatory and Anticancer Properties In Vitro.

Hasan Tarek, Seung Sik Cho, Md Selim Hossain, Jin Cheol Yoo.

Oxidative damage and inflammation are among the very significant aspects interrelated with cancer and other degenerative diseases. In this study, we investigated the biological activities of a 25 kDa protease (SH21) that was purified from Bacillus siamensis. SH21 exhibited very powerful antioxidant and reactive oxygen species (ROS) generation inhibition activity in a dose-dependent approach. The mRNA and protein levels of antioxidant enzymes such as superoxide dismutase 1 (SOD1), catalase (CAT), and glutathione peroxidase 1 (GPx-1) were enhanced in the SH21-treated sample. SH21 also increased the transcriptional and translational activities of NF-E2-related factor 2 (Nrf2) with the subsequent development of detoxifying enzyme heme oxygenase-1 (HO-1). In addition, SH21 showed potential anti-inflammatory activity via inhibition of nitric oxide (NO) and proinflammatory cytokines, such as TNF-α, IL-6, and IL-1β, production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. At concentrations of 60, 80, and 100 μg/mL, SH21 potentially suppressed nitric oxide synthase (iNOS) and cytokine gene expressions. Furthermore, SH21 significantly released lactate dehydrogenase (LDH) enzyme in cancer cell supernatant in a concentration-dependent manner and showed strong activity against three tested cancer cell lines, including HL-60, A549, and Hela. Our results suggest that SH21 has effective antioxidant, anti-inflammatory, and anticancer effects and could be an excellent therapeutic agent against inflammation-related diseases.

Keywords: anti-inflammatory; anticancer; antioxidants; oxidative damage; protease SH21

DOI: https://doi.org/10.3390/cells12172190