bims-nurfca 2024-06-23 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2024–06–23
six papers selected by
Caner Geyik, Istinye University

CPEB1 Controls NRF2 Proteostasis and Ferroptosis Susceptibility in Pancreatic Cancer.
WNK1 Interaction with KEAP1 Promotes NRF2 Stabilization to Enhance the Oxidative Stress Response in Hepatocellular Carcinoma.
Potential mechanisms of cancer prevention and treatment by sulforaphane, a natural small molecule compound of plant-derived.
Transcriptional Up-Regulation of FBXW7 by KCa1.1 K+ Channel Inhibition through the Nrf2 Signaling Pathway in Human Prostate Cancer LNCaP Cell Spheroid Model.
Shen-Qi-Ling-Bi Decoction Inhibits Colorectal Cancer Cell Growth by Inducing Ferroptosis Through Inactivation of PI3K/AKT Signaling Pathway.
Targeting TRIM40 signaling reduces esophagus cancer development: A mechanism involving in protection of oroxylin A.

Int J Biol Sci. 2024 ;20(8): 3156-3172

CPEB1 Controls NRF2 Proteostasis and Ferroptosis Susceptibility in Pancreatic Cancer.

Shuxia Zhang, Jingnan Huang, Zhangzhang Lan, Yanlin Xiao, Youyou Liao, Shiva Basnet, Piying Huang, Yunze Li, Jingyu Yan, Yuling Sheng, Wenwen Zhou, Qi Liu, Haoyuan Tan, Yi Tan, Leyong Yuan, Lisheng Wang, Lingyun Dai, Wenyong Zhang, Changzheng Du.

  Pancreatic cancer is the deadliest malignancy with a poor response to chemotherapy but is potentially indicated for ferroptosis therapy. Here we identified that cytoplasmic polyadenylation element binding protein 1 (CPEB1) regulates NRF2 proteostasis and susceptibility to ferroptosis in pancreatic ductal adenocarcinoma (PDAC). We found that CPEB1 deficiency in cancer cells promotes the translation of p62/SQSTM1 by facilitating mRNA polyadenylation. Consequently, upregulated p62 enhances NRF2 stability by sequestering KEAP1, an E3 ligase for proteasomal degradation of NRF2, leading to the transcriptional activation of anti-ferroptosis genes. In support of the critical role of this signaling cascade in cancer therapy, CPEB1-deficient pancreatic cancer cells display higher resistance to ferroptosis-inducing agents than their CPEB1-normal counterparts in vitro and in vivo. Furthermore, based on the pathological evaluation of tissue specimens from 90 PDAC patients, we established that CPEB1 is an independent prognosticator whose expression level is closely associated with clinical therapeutic outcomes in PDAC. These findings identify the role of CPEB1 as a key ferroptosis regulator and a potential prognosticator in pancreatic cancer.

Keywords:  CPEB1; NRF2; ferroptosis; p62/SQSTM1; pancreatic cancer

DOI:  https://doi.org/10.7150/ijbs.95962
Cancer Res. 2024 Jun 17.

WNK1 Interaction with KEAP1 Promotes NRF2 Stabilization to Enhance the Oxidative Stress Response in Hepatocellular Carcinoma.

Li Li, Dacheng Xie, Shijun Yu, Muyuan Ma, Kailing Fan, Jingde Chen, Mengxi Xiu, Keping Xie, Yandong Li, Gao Yong.

Cellular oxidative stress plays a key role in the development and progression of hepatocellular carcinoma (HCC). A better understanding of the processes that regulate reactive oxygen species (ROS) homeostasis could uncover improved strategies for treating HCC. Here, we identified WNK1 as an antioxidative factor and therapeutic target in HCC. In human HCC, WNK1 expression was increased and correlated with poor patient prognosis. WNK1 knockdown significantly inhibited cell proliferation and xenograft tumor growth. Mechanistically, WNK1 competed with NRF2 for binding to the partial Kelch domain of KEAP1, reducing NRF2 ubiquitination and promoting NRF2 accumulation and nuclear translocation to increase antioxidant response. WNK1 silencing increased H2O2-induced apoptosis and inhibited cell growth by elevating reactive oxygen species (ROS) levels, which could be rescued by treatment with the antioxidant N-acetylcysteine (NAC) and NRF2 activator tert-butylhydroquinone (tBHQ). Liver-specific WNK1 knockout mouse models of HCC substantiated that WNK1 promoted HCC development by regulating ROS levels. WNK463, an inhibitor of the WNK kinase family, suppressed HCC progression and altered the redox status. These findings suggest that WNK1 plays a critical role in HCC development and progression and that the WNK1-oxidative stress axis may be a promising therapeutic target for HCC.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-1167
Mol Med. 2024 Jun 21. 30(1): 94

Potential mechanisms of cancer prevention and treatment by sulforaphane, a natural small molecule compound of plant-derived.

Pengtao Liu, Bo Zhang, Yuanqiang Li, Qipeng Yuan.

  Despite recent advances in tumor diagnosis and treatment technologies, the number of cancer cases and deaths worldwide continues to increase yearly, creating an urgent need to find new methods to prevent or treat cancer. Sulforaphane (SFN), as a member of the isothiocyanates (ITCs) family, which is the hydrolysis product of glucosinolates (GLs), has been shown to have significant preventive and therapeutic cancer effects in different human cancers. Early studies have shown that SFN scavenges oxygen radicals by increasing cellular defenses against oxidative damage, mainly through the induction of phase II detoxification enzymes by nuclear factor erythroid 2-related factor 2 (Nrf2). More and more studies have shown that the anticancer mechanism of SFN also includes induction of apoptotic pathway in tumor cells, inhibition of cell cycle progression, and suppression of tumor stem cells. Therefore, the application of SFN is expected to be a necessary new approach to treating cancer. In this paper, we review the multiple molecular mechanisms of SFN in cancer prevention and treatment in recent years, which can provide a new vision for cancer treatment.

Keywords:  Cancer; Combination therapy; Molecular mechanism; Natural small molecule compound; Sulforaphane

DOI:  https://doi.org/10.1186/s10020-024-00842-7
Int J Mol Sci. 2024 May 30. pii: 6019. [Epub ahead of print]25(11):

Transcriptional Up-Regulation of FBXW7 by KCa1.1 K+ Channel Inhibition through the Nrf2 Signaling Pathway in Human Prostate Cancer LNCaP Cell Spheroid Model.

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

  The tumor suppressor gene F-box and WD repeat domain-containing (FBXW) 7 reduces cancer stemness properties by promoting the protein degradation of pluripotent stem cell markers. We recently demonstrated the transcriptional repression of FBXW7 by the three-dimensional (3D) spheroid formation of several cancer cells. In the present study, we found that the transcriptional activity of FBXW7 was promoted by the inhibition of the Ca2+-activated K+ channel, KCa1.1, in a 3D spheroid model of human prostate cancer LNCaP cells through the Akt-Nrf2 signaling pathway. The transcriptional activity of FBXW7 was reduced by the siRNA-mediated inhibition of the CCAAT-enhancer-binding protein C/EBP δ (CEBPD) after the transfection of miR223 mimics in the LNCaP spheroid model, suggesting the transcriptional regulation of FBXW7 through the Akt-Nrf2-CEBPD-miR223 transcriptional axis in the LNCaP spheroid model. Furthermore, the KCa1.1 inhibition-induced activation of FBXW7 reduced (1) KCa1.1 activity and protein levels in the plasma membrane and (2) the protein level of the cancer stem cell (CSC) markers, c-Myc, which is a molecule degraded by FBXW7, in the LNCaP spheroid model, indicating that KCa1.1 inhibition-induced FBXW7 activation suppressed CSC conversion in KCa1.1-positive cancer cells.

Keywords:  C/EBP; Ca2+-activated K+ channel; FBXW7; KCa1.1; Nrf2; c-Myc; cancer stemness; miR223; protein degradation; spheroid

DOI:  https://doi.org/10.3390/ijms25116019
DNA Cell Biol. 2024 Jun 17.

Shen-Qi-Ling-Bi Decoction Inhibits Colorectal Cancer Cell Growth by Inducing Ferroptosis Through Inactivation of PI3K/AKT Signaling Pathway.

Lin Liu, Guanlong Ye, Wei Huang, Yang He, Donghao Xie.

  Colorectal cancer (CRC) is a common malignancy with poor prognosis. Shen-Qi-Ling-Bi Decoction (SQLB), a classic traditional Chinese medicine (TCM) formula, was found to exert antitumor effects in CRC. This study aimed to explore the biological functions of SQLB in CRC. Cell Counting Kit 8 (CCK-8), wound healing, and transwell invasion assays in vitro were used to evaluate the antitumor effects of SQLB in CRC cells. In addition, ferroptosis in CRC cells was determined by evaluating Fe2+ content and lipid ROS, MDA, and GSH levels. SQLB treatment partially reduced CRC cell proliferation, migration, and invasion; however, a ferroptosis inhibitor, ferrostatin-1 (Fer-1), abolished these effects. In addition, SQLB treatment triggered CRC cell ferroptosis, as evidenced by increased Fe2+, lipid ROS, and MDA levels and decreased GSH levels; conversely, these levels were reversed by Fer-1. Furthermore, SQLB notably suppressed tumor growth in nude mice in vivo. Meanwhile, SQLB decreased phosphorylated PI3K and AKT levels, downregulated Nrf2, GPX4, and SLC7A11 levels, and upregulated ACSL4 levels in CRC cells and in tumor tissues; however, these effects were reversed by Fer-1. Collectively, SQLB inhibited CRC cell proliferation, invasion, and migration by triggering ferroptosis through inactivation of the PI3K/AKT signaling pathway. These findings demonstrate a novel mechanism of action for SQLB in the treatment of CRC.

Keywords:  colorectal cancer; ferroptosis; ferrostatin-1; traditional Chinese medicine

DOI:  https://doi.org/10.1089/dna.2023.0434
Int Immunopharmacol. 2024 Jun 19. pii: S1567-5769(24)00882-8. [Epub ahead of print]137 112362

Targeting TRIM40 signaling reduces esophagus cancer development: A mechanism involving in protection of oroxylin A.

Yanlei Ji, Fengxiang Li, Hui Zhang, Linke Yang, Yan Yi, Lan Wang, Hua Chen, Yong Zhang, Zhengqiang Yang.

  Oroxylin A (OA), a naturally active O-methylated flavone derived from Scutellaria baicalensis, is regarded as a potential drug with strong anticancer effects. Unfortunately, our understanding of the antineoplastic mechanism of oral exposure to such flavonoids is inadequate. Growing evidence has confirmed the important role of OA in the regulation of oxidative stress- and inflammatory-response-induced tissue injury. However, it remains unknown whether OA is capable of mitigating esophagus cancer (EC) progression and its potential molecular mechanism. Furthermore, the tripartite motif containing 40 (TRIM40) is a ubiquitin ligase that mediates the immune response. The potential molecular function of TRIM40 in regulating EC is largely unknown. We confirmed that OA-triggered oxidative stress markedly upregulates TRIM40. During the OA challenge, increased TRIM40 reduced oxidative stress and promoted the ER stress response. Inversely, deletion of TRIM40 facilitated oxidative stress and blocked cancer cell growth in vivo and in vitro. Mechanistically, in response to OA treatment, TRIM40 directly interacts with Keap1 and promotes ubiquitin-proteasome degradation, thus leading to the promotion of Nrf2 nuclear translocation and its downstream cascade activation, which increases antioxidant defense and cell survival. TRIM40 expression was positively correlated with Nrf2 expression and negatively associated with Keap1 expression in EC xenografts and human specimens. In addition, high TRIM40 expression correlates with poor patient survival in EC. The findings suggested that oral exposure to OA significantly mitigates EC development by targeting TRIM40 activity. These findings further elucidated the potential role of TRIM40 in EC progression by mediating Keap1 degradation, which could be considered a therapeutic target for the treatment of such a disease.

Keywords:  Esophagus cancer (EC); NRF2; Oroxylin A; Oxidative stress; TRIM40

DOI:  https://doi.org/10.1016/j.intimp.2024.112362