bims-nurfca 2023-04-23 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2023–04–23
nine papers selected by
Caner Geyik, Istinye University

Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression.
NFR2/ABC transporter axis in drug resistance of breast cancer cells.
Effects of the juçara fruit (Euterpe edulis Martius) pulp and lyophilized extract on NRF2, KEAP1, SOD1, and GPX2 expression in human colorectal cancer cell lines.
The role of the Nrf2/GSH antioxidant system in cisplatin resistance in malignant rhabdoid tumours.
Role of ionizing radiation activated NRF2 in lung cancer radioresistance.
Downregulation of lncRNA SLC7A11-AS1 decreased the NRF2/SLC7A11 expression and inhibited the progression of colorectal cancer cells.
Overall survival in patients with advanced non-small cell lung cancer with KRAS G12C mutation with or without STK11 and/or KEAP1 mutations in a real-world setting.
Cancer Protective Role of Selected Dietary Polyphenols via Modulating Keap1/Nrf2/ARE and Interconnected Signaling Pathways.
Polyphyllin I suppresses the gastric cancer growth by promoting cancer cell ferroptosis.

Cancer Res. 2023 Apr 16. pii: CAN-22-3848. [Epub ahead of print]

Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression.

Janine M DeBlasi, Aimee Falzone, Samantha Caldwell, Nicolas Prieto-Farigua, Justin R Prigge, Edward E Schmidt, Iok In Christine Chio, Florian A Karreth, Gina M DeNicola.

Mutations in the KEAP1-NRF2 pathway occur in up to a third of non-small cell lung cancer (NSCLC) cases and often confer resistance to therapy and poor outcomes. Here, we developed murine alleles of the KEAP1 and NRF2 mutations found in human NSCLC and comprehensively interrogated their impact on tumor initiation and progression. Chronic NRF2 stabilization by Keap1 or Nrf2 mutation was not sufficient to induce tumorigenesis, even in the absence of tumor suppressors p53 or LKB1. When combined with KrasG12D/+, constitutive NRF2 activation promoted lung tumor initiation and early progression of hyperplasia to low-grade tumors but impaired their progression to advanced-grade tumors, which was reversed by NRF2 deletion. Finally, NRF2 overexpression in KEAP1 mutant human NSCLC cell lines was detrimental to cell proliferation, viability, and anchorage-independent colony formation. Collectively, these results establish the context-dependence and activity threshold for NRF2 during the lung tumorigenic process.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-3848
Mol Biol Rep. 2023 Apr 20.

NFR2/ABC transporter axis in drug resistance of breast cancer cells.

Zinat Sargazi, Yalda Yazdani, Amir Tahavvori, Hamed Rahmani Youshanlouei, Vahid Alivirdiloo, Elmira Aboutalebi Vand Beilankouhi, Mohammad Valilo.

  Breast cancer is one of the most serious malignancies among women, accounting for about 12% of all cancers. The inherent complexity and heterogeneity of breast cancer results in failure to respond to treatment in the advanced stages of the disease. Breast cancer is caused by several genetic and environmental factors. One of the significant factors involved in the development of breast cancer is oxidative stress, which is generally regulated by nuclear factor erythroid 2-related factor 2 (NRF2). The level of NRF2 expression is low in healthy cells, which maintains the balance of the antioxidant system; however, its expression is higher in cancer cells, which have correlation characteristics such as angiogenesis, stem cell formation, drug resistance, and metastasis. Drug resistance increases with the upregulation of NRF2 expression, which contributes to cell protection. NRF2 controls this mechanism by increasing the expression of ATP-binding cassettes (ABCs). Considering the growing number of studies in this field, we aimed to investigate the relationship between NRF2 and ABCs, as well as their role in the development of drug resistance in breast cancer.

Keywords:  ATP-binding cassette (ABC); Breast cancer; Drug resistance; Nuclear factor erythroid 2-related factor 2 (NRF2)

DOI:  https://doi.org/10.1007/s11033-023-08384-7
Braz J Med Biol Res. 2023 ;pii: S0100-879X2023000100629. [Epub ahead of print]56 e12558

Effects of the juçara fruit (Euterpe edulis Martius) pulp and lyophilized extract on NRF2, KEAP1, SOD1, and GPX2 expression in human colorectal cancer cell lines.

L A Milholli, J Dalbó, C V M S Couto, M M Oliveira, J G Dos Santos, G T Peterle, A B Archanjo, P I Silva, J N Boeloni, F D Nunes, A M Á da Silva, L O Trivilin.

We investigated the effects of the juçara fruit (Euterpe edulis Martius) pulp and lyophilized extract on the expression of cytoprotective genes nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2), kelch-like ECH-associated protein 1 (KEAP1), superoxide dismutase (SOD1), and glutathione peroxidase (GPX2) in human colorectal cancer cell lines (HT-29 and Caco-2). Cells were cultured for 24 h in Dulbecco's Modified Eagle's Medium containing juçara fruit pulp (5, 10, or 50 mg/mL) or lyophilized extract (0.05, 0.1, or 0.5 mg/mL), and gene expression was quantified using real-time quantitative reverse transcription polymerase chain reaction. All studied genes showed significant variation in gene expression among different concentrations of pulp or lyophilized extract. Overall, the expression of the selected genes decreased in both cell lines following exposure to the pulp or lyophilized extract in a dose-dependent manner for most of the concentrations studied. In summary, our study showed that the compounds in juçara fruit inhibited the expression of cytoprotective genes associated with the antioxidant response and that, although not cytotoxic at the concentrations studied, they could potentially block the activation of the NRF2/KEAP1 pathway.

DOI: https://doi.org/10.1590/1414-431X2023e12558
J Cancer Res Clin Oncol. 2023 Apr 20.

The role of the Nrf2/GSH antioxidant system in cisplatin resistance in malignant rhabdoid tumours.

Patricia Hannon Barroeta, Maureen J O'Sullivan, Daniela M Zisterer.

   PURPOSE: Malignant rhabdoid tumour (MRT) is a rare and aggressive childhood malignancy that occurs in the kidneys or central nervous system and is associated with very poor prognosis. Chemoresistance is a major issue in the treatment of this malignancy leading to an urgent need for a greater understanding of its underlying mechanisms in MRT and novel treatment strategies for MRT patients. The balance between oxidative stress mediated by reactive oxygen species (ROS) and the antioxidant system has become a subject of interest in cancer therapy research. Studies have implicated key players of the antioxidant system in chemotherapeutic including the well-known antioxidant glutathione (GSH) and the transcription factor nuclear erythroid-related factor-2 (Nrf2). METHODS: This study evaluated the role of these components in the response of MRT cells to treatment with the commonly used chemotherapeutic agent, cisplatin.
RESULTS: This study characterised the basal levels of GSH, ROS and Nrf2 in a panel of MRT cell lines and found a correlation between the expression profile of the antioxidant defence system and cisplatin sensitivity. Results showed that treatment with ROS scavenger N-acetylcysteine (NAC) protected cells from cisplatin-induced ROS and apoptosis. Interestingly, depleting GSH levels with the inhibitor buthionine sulphoximine (BSO) enhanced cisplatin-induced ROS and sensitised cells to cisplatin. Lastly, targeting Nrf2 with the small molecule inhibitor ML385 or by siRNA diminished GSH levels, enhanced ROS and sensitised resistant MRT cells to cisplatin.
CONCLUSIONS: These results suggest that targeting the Nrf2/GSH antioxidant system may present a novel therapeutic strategy to combat chemoresistance in rhabdoid tumours.

Keywords:  Apoptosis; Chemoresistance; Glutathione; Malignant rhabdoid tumour; Nuclear erythroid-related factor-2; Reactive oxygen species

DOI:  https://doi.org/10.1007/s00432-023-04734-x
Int J Biol Macromol. 2023 Apr 17. pii: S0141-8130(23)01370-3. [Epub ahead of print] 124476

Role of ionizing radiation activated NRF2 in lung cancer radioresistance.

Qianqian Xu, Peiyu Zhang, Xiaoyang Han, Huwei Ren, Weiyue Yu, Wei Hao, Bowen Luo, Muhammad Imran Khan, Chen Ni.

  Radiotherapies are commonly used to target remaining tumor niches after surgery of solid tumors but are restricted due to therapeutic resistance. Several pathways of radioresistance have been reported in various cancers. This study investigates the pivotal role of Nuclear factor-erythroid 2-related factor 2 (NRF2) in the activation of DNA damage repair in lung cancer cells after x-rays exposure. To explore the NRF2 activation after ionizing irradiations, this study uses a knockdown of NRF2, which shows potential DNA damage after x-rays irradiation in lung cancers. This work further shows that NRF2 knockdown disrupts damaged DNA repair by inhibiting DNA-dependent protein kinase catalytic subunit. At the same time, NRF2 knockdown by shRNA considerably disparate homologous recombination by interfering with Rad51 expression. Further investigation of the associated pathway reveals that NRF2 activation mediates DNA damage response via the mitogen-activated protein kinase (MAPK) pathway as the knockout of NRF2 directly enhances intracellular MAPK phosphorylation. Similarly, both NAC and constitutive knockout of NRF2 disrupt DNA-dependent protein kinase catalytic subunit, while NRF2 knockout failed to upregulate Rad51 expression after irradiation in-vivo. Taken together, these findings advocate NRF2 plays a critical role in the development of radioresistance by upregulating DNA damage response via the MAPK pathway, which can be of great significance.

Keywords:  DNA damage response; DNA-dependent protein kinase; Mitogen-activated protein kinase; NRF2; Radioresistance

DOI:  https://doi.org/10.1016/j.ijbiomac.2023.124476
PeerJ. 2023 ;11 e15216

Downregulation of lncRNA SLC7A11-AS1 decreased the NRF2/SLC7A11 expression and inhibited the progression of colorectal cancer cells.

Tian Wang, Si Liang, Yajing Li, Xiyu Wang, Hongjie Wang, Jiguang Guo, Ming Li.

  Colorectal cancer (CRC) is ranked as the second leading cause of cancer-related death worldwide. Many abnormally expressed long non-coding RNAs (lncRNAs) in CRC were identified with the development of next-generation sequencing, most functions of which are largely unclear. In this study, we report that the lncRNA SLC7A11-AS1 was significantly overexpressed in CRC by analyzing TCGA database and 6 pairs of clinical samples. High SLC7A11-AS1 level was related to poor CRC overall survival and SLC7A11-AS1 knockdown could inhibit the proliferation, migration and invasion of CRC cell lines. Furthermore, we found there was a positive correlation between the expression of SLC7A11-AS1 and its' sense transcript SLC7A11. In HCT-8 cells, SLC7A11-AS1 knockdown decreased expression of both SLC7A11 and the nuclear level of NRF2, which happens to be the activator of SLC7A11 transcription. Interestingly, in SLC7A11-AS1 overexpressed CRC tissues, SLC7A11 and NRF2 were also upregulated. Moreover, the ROS levels increased with SLC7A11-AS1 knockdown in HCT-8 cells. And the down regulated expression of SLC7A11 and lower ROS level causing by SLC7A11-AS1 knocked down could be relieved by overexpressed NRF2. These results suggested that upregulated SLC7A11-AS1 might promote the formation and progression of CRC by increasing the expression of NRF2 and SLC7A11, which decreases the ROS level in cancer cells. Therefore, SLC7A11-AS1 could be a potential therapeutic target and diagnostic marker of CRC.

Keywords:  Colorectal cancer; NRF2; Reactive oxygen species; SLC7A11; SLC7A11-AS1

DOI:  https://doi.org/10.7717/peerj.15216
BMC Cancer. 2023 Apr 17. 23(1): 352

Overall survival in patients with advanced non-small cell lung cancer with KRAS G12C mutation with or without STK11 and/or KEAP1 mutations in a real-world setting.

Cristina Julian, Navdeep Pal, Anda Gershon, Marie Evangelista, Hans Purkey, Peter Lambert, Zhen Shi, Qing Zhang.

   BACKGROUND: KRAS mutations occur frequently in advanced non-small cell lung cancer (aNSCLC); the G12C mutation is the most prevalent. Alterations in STK11 or KEAP1 commonly co-occur with KRAS mutations in aNSCLC. Using real-world data, we assessed the effect of KRAS G12C mutation with or without STK11 and/or KEAP1 mutations on overall survival (OS) in patients with aNSCLC receiving cancer immunotherapy (CIT), chemotherapy, or both in first line (1L) and second line (2L).
METHODS: Patients diagnosed with aNSCLC between January 2011 and March 2020 in a clinico-genomic database were included. Cox proportional hazards models adjusted for left truncation, baseline demographics and clinical characteristics were used to analyze the effect of STK11 and/or KEAP1 co-mutational status on OS in patients with KRAS wild-type (WT) or G12C mutation.
RESULTS: Of 2715 patients with aNSCLC without other actionable driver mutations, 1344 (49.5%) had KRAS WT cancer, and 454 (16.7%) had KRAS G12C-positive cancer. At 1L treatment start, significantly more patients with KRAS G12C-positive cancer were female, smokers, and had non-squamous histology, a higher prevalence of metastasis and programmed death-ligand 1 positivity than those with KRAS WT cancer. Median OS was comparable between patients with KRAS G12C-positive and KRAS WT cancer when receiving chemotherapy or combination CIT and chemotherapy in the 1L or 2L. Median OS was numerically longer in patients with KRAS G12C vs KRAS WT cancer treated with 1L CIT (30.2 vs 10.6 months, respectively) or 2L CIT (11.3 vs 7.6 months, respectively). Co-mutation of STK11 and KEAP1 was associated with significantly shorter OS in patients receiving any type of 1L therapy, regardless of KRAS G12C mutational status.
CONCLUSIONS: This real-world study showed that patients with KRAS G12C-positive or KRAS WT cancer have similar OS in the 1L or 2L when treated with chemotherapy or combination CIT and chemotherapy. In contrast to aNSCLC patients with EGFR or ALK driver mutations, patients with KRAS G12C-positive cancer may benefit from CIT monotherapy. Co-mutation of STK11 and KEAP1 was associated with significantly shorter survival, independent of KRAS G12C mutational status, reflecting the poor prognosis and high unmet need in this patient population.

Keywords:  Chemotherapy; Immunotherapy; KEAP1; KRAS G12C; Metastasis; Non-small cell lung cancer; STK11

DOI:  https://doi.org/10.1186/s12885-023-10778-6
Nutr Cancer. 2023 Apr 20. 1-38

Cancer Protective Role of Selected Dietary Polyphenols via Modulating Keap1/Nrf2/ARE and Interconnected Signaling Pathways.

Md Arman Islam, Maisha Maliha Medha, Akhlak Un Nahar, Md Abdullah Al Fahad, Md Afjalus Siraj, Veronique Seidel.

The Kelch-like ECH associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (ARE) signaling pathway is considered a master regulator of the cellular response against oxidative stress. Numerous studies have investigated the role of Keap1/Nrf2/ARE in the different stages of cancer development. A comprehensive literature search using the Google Scholar, PubMed and Science Direct databases was performed to retrieve information related to the cancer protective role of 21 selected dietary polyphenols via modulation of Keap1/Nrf2/ARE and interconnected signaling pathways/proteins (MAPK/ERK1/2, PI3K/Akt, PKD, JNKs, AMPK, NF-κB). Information on the anti-inflammatory and cytoprotective effects caused by the selected dietary polyphenols following Keap1/Nrf2/ARE modulation was also collected. The majority of the studies analyzed in this review demonstrated the cancer protective role of the selected polyphenols mostly in-vitro. Limited work was performed in-vivo and only one of the selected polyphenols was subjected to a clinical trial. It is hoped that this review will encourage further in-vivo studies to confirm the cancer protective role of methyleugenol, carnosol, and catechin, as well as further clinical trials to unambiguously establish whether the consumption of dietary polyphenols impacts on the incidence and progression of cancers in humans.

DOI: https://doi.org/10.1080/01635581.2023.2183546
Front Pharmacol. 2023 ;14 1145407

Polyphyllin I suppresses the gastric cancer growth by promoting cancer cell ferroptosis.

Fang Zheng, Yeshu Wang, Qunfang Zhang, Qiuyuan Chen, Chun-Ling Liang, Huazhen Liu, Feifei Qiu, Yuchao Chen, Haiding Huang, Weihui Lu, Zhenhua Dai.

  Background: Ferroptosis is a new form of regulated cell death characterized by the accumulation of iron-dependent lipid peroxides and membrane damages. Recent studies have identified an important role for cancer cell ferroptosis in antitumor therapy. On the other hand, polyphyllin I (PPI) has been reported to exert antitumor effects on some types of cancers. However, it remains unknown whether or not PPI regulates cancer cell ferroptosis. Methods: Two types of human gastric cancer cells (AGS and MKN-45) were used to establish tumor xenograft models in nude mice that were treated with polyphyllin I (PPI) to observe tumor growth, while cells also were cultured for in vitro studies. Ferroptosis, based on the intracellular ROS/lipid ROS production and accumulation of ferrous ions, was detected using a fluorescence microscope and flow cytometer, while the expression of NRF2/FTH1 was measured using Western blotting assays. Results: Here we found that PPI inhibited the gastric cancer growth in vivo and in vitro while increasing the intracellular reactive oxygen species (ROS)/lipid peroxides and ferrous ions in the gastric cancer cells. PPI also decreased the levels of nuclear factor erythroid 2-related factor 2 (NRF2) and ferritin heavy chain 1 (FTH1) in gastric cancer cells in vitro. Moreover, liproxstain-1, an inhibitor of cell ferroptosis, mostly reversed the cell ferroptosis and tumor growth arrest induced by PPI. Finally, the effects of PPI on cancer cell ferroptosis were diminished by the overexpression of NRF2. Conclusion: For the first time, our results have demonstrated that PPI exerts its antitumor activity on the gastric cancer by, at least partially, inducing cancer cell ferroptosis via regulating NRF2/FTH1 pathway. These findings may be implicated for clinical replacement therapy of the gastric cancer.

Keywords:  NRF2; anticancer drug; ferroptosis; gastric cancer; polyphyllin I

DOI:  https://doi.org/10.3389/fphar.2023.1145407