bims-nurfca 2024-08-25 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2024‒08‒25
ten papers selected by
Caner Geyik, Istinye University

The deubiquitinating enzyme USP35 regulates the stability of NRF2 protein.
Hsp90α promotes chemoresistance in pancreatic cancer by regulating Keap1-Nrf2 axis and inhibiting ferroptosis.
NRF2 inhibits RSL3 induced ferroptosis in gastric cancer through regulation of AKR1B1.
Targeting ROS-sensing Nrf2 potentiates anti-tumor immunity of intratumoral CD8+ T and CAR-T cells.
Nrf2-mediated adenylosuccinate lyase promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma cells through ferroptosis escape.
TP53 co-mutations in advanced lung adenocarcinoma: comparative bioinformatic analyses suggest ambivalent character on overall survival alongside KRAS, STK11 and KEAP1 mutations.
Targeting Nrf2/PHKG2 axis to enhance radiosensitivity in NSCLC.
Prebiotic stachyose inhibits PRDX5 activity and castration-resistant prostate cancer development.
Aurantio‑obtusin regulates lipogenesis and ferroptosis of liver cancer cells through inhibiting SCD1 and sensitizing RSL3.
Muscle-derived IL-1β regulates EcSOD expression via the NBR1-p62-Nrf2 pathway in muscle during cancer cachexia.

Open Life Sci. 2024 ;19(1): 20220935

The deubiquitinating enzyme USP35 regulates the stability of NRF2 protein.

Dian Zhang, Jiawen Li, Chao Zhang, Jinliang Xue, Peihao Li, Kai Shang, Xiao Zhang, Baoping Lang.

  Many cancers exhibit resistance to chemotherapy, resulting in a poor prognosis. The transcription factor NRF2, activated in response to cellular antioxidants, plays a crucial role in cell survival, proliferation, and resistance to chemotherapy. This factor may serve as a promising target for therapeutic interventions in esophageal carcinoma. Recent research suggests that NRF2 activity is modulated by ubiquitination mediated by the KEAP1-CUL3 E3 ligase complex, highlighting the importance of deubiquitination. However, the specific deubiquitinase responsible for regulating NRF2 in esophageal cancer remains unknown. In this study, a novel regulator of the NRF2 protein, Ubiquitin-Specific Protease 35 (USP35), has been identified. Mechanistically, USP35 modulates NRF2 stability through enzymatic deubiquitination. USP35 interacts with NRF2 and facilitates its deubiquitination. Knockdown of USP35 leads to a notable increase in NRF2 levels and enhances the sensitivity of cells to chemotherapy. These findings suggest that the USP35-NRF2 axis is a key player in the regulation of therapeutic strategies for esophageal cancer.

Keywords:  NRF2; USP35; chemoresistance; deubiquitylation; esophageal cancer

DOI:  https://doi.org/10.1515/biol-2022-0935
Acta Biochim Biophys Sin (Shanghai). 2024 Aug 23.

Hsp90α promotes chemoresistance in pancreatic cancer by regulating Keap1-Nrf2 axis and inhibiting ferroptosis.

Bin Liu, Zhiyuan Chen, Zhaoxing Li, Xinya Zhao, Weigang Zhang, Ao Zhang, Longxing Wen, Xiaoming Wang, Shuying Zhou, Daohai Qian.

  Chemoresistance is the primary reason for poor prognosis in patients with pancreatic cancer (PC). Recent studies have indicated that ferroptosis may improve chemoresistance, but the underlying mechanisms remain unclear. In this study, significant upregulation of heat shock protein 90α (Hsp90α) expression is detected in the peripheral blood and tissue samples of patients with chemoresistant PC. Further studies reveal that Hsp90α promotes the proliferation, migration, and invasion of a chemoresistant pancreatic cell line (Panc-1-gem) by suppressing ferroptosis. Hsp90α competitively binds to Kelch-like ECH-associated protein 1 (Keap1), liberating nuclear factor erythroid 2-related factor 2 (Nrf2) from Keap1 sequestration. Nrf2 subsequently translocates into the nucleus and activates the glutathione peroxidase 4 (GPX4) pathway, thereby suppressing ferroptosis. This process further worsens the chemoresistance of PC cells. This study provides valuable insight into potential molecular targets to overcome chemoresistance in PC. It sheds light on the intricate mechanisms linking Hsp90α and ferroptosis to chemoresistance in PC and provides a theoretical foundation for the development of novel therapeutic strategies.

Keywords:  Keap1-Nrf2 axis; ferroptosis; heat shock protein 90α; pancreatic cancer chemoresistance

DOI:  https://doi.org/10.3724/abbs.2024138
Exp Cell Res. 2024 Aug 16. pii: S0014-4827(24)00301-X. [Epub ahead of print] 114210

NRF2 inhibits RSL3 induced ferroptosis in gastric cancer through regulation of AKR1B1.

Xin Li, Jianxin Qian, Jiahua Xu, Haoran Bai, Jinzu Yang, Ling Chen.

  Gastric cancer is a malignant tumor associated with a high mortality rate. Recently, emerging evidence has shown that ferroptosis, a regulated form of cell death induced by iron (Fe)-dependent lipid peroxidation. Nuclear factor E2 related factor 2 (NRF2) is a key regulator of intracellular oxidation homeostasis that plays a pivotal role in controlling lipid peroxidation, which is closely related to the process of ferroptosis. However, the molecular mechanism of NRF2 on ferroptosis remains to be investigated in gastric cancer. In our study, NRF 2 was found to transcriptionally activate Aldo-keto reductase 1 member B1 (AKR1B1) expression in gastric cancer. AKR1B1 is involved in the regulation of lipid metabolism by removing the aldehyde group of glutathione. We found that AKR1B1 is highly expressed in gastric cancer and is associated with a poor prognosis of the patients. In vitro experiments found that AKR1B1 has the ability to promote the proliferation and invasion of gastric cancer cells. AKR1B1 inhibited RSL3-induced ferroptosis in gastric cancer by reducing reactive oxygen species accumulation and lipid peroxidation, as well as decreasing intracellular ferrous ion and malondialdehyde expression and increasing glutathione expression. Our study demonstrated that AKR1B1 resisted RSL3-induced ferroptosis by regulating GPX4, PTGS2 and ACSL4, which was further demonstrated in a xenograft nude mouse model. Our work reveals a critical role for the AKR1B1 in the resistance to RSL3-induced ferroptosis in gastric cancer.

Keywords:  AKR1B1; NRF2; ferroptosis; gastric cancer

DOI:  https://doi.org/10.1016/j.yexcr.2024.114210
Mol Ther. 2024 Aug 20. pii: S1525-0016(24)00541-0. [Epub ahead of print]

Targeting ROS-sensing Nrf2 potentiates anti-tumor immunity of intratumoral CD8+ T and CAR-T cells.

Yuna Jo, Ju A Shim, Jin Woo Jeong, Hyori Kim, So Min Lee, Juhee Jeong, Segi Kim, Sun-Kyoung Im, Donghoon Choi, Byung Ha Lee, Yun Hak Kim, Chi Dae Kim, Chan Hyuk Kim, Changwan Hong.

Cytotoxic T lymphocytes (CTLs) play a crucial role in cancer rejection. However, CTLs encounter dysfunction and exhaustion in the immunosuppressive tumor microenvironment (TME). Although the reactive oxygen species (ROS)-rich TME attenuates the CTL function, the underlying molecular mechanism remains poorly understood. The nuclear factor-erythroid 2-related-2 (Nrf2) is ROS-responsible factor implicated in increasing susceptibility to cancer progression. Therefore, we examined how Nrf2 is involved in anti-tumor responses of CD8+ T and chimeric antigen receptor (CAR)-T cells under ROS-rich TME. Here, we demonstrated that tumor growth in Nrf2-/- mice was significantly controlled and was reversed by T cell depletion and further confirmed that Nrf2 deficiency in T cells promotes anti-tumor responses using adoptive transfer model of antigen-specific CD8+ T cells. Nrf2-deficient CTLs are resistant to ROS, and their effector functions are sustained in TME. Furthermore, Nrf2 knockdown in human CAR-T cells enhanced the survival and function of intratumoral CAR-T cells in solid tumor xenograft model and effectively controlled tumor growth. ROS-sensing Nrf2 inhibits the anti-tumor T cell responses, indicating that Nrf2 may be a potential target for T cell immunotherapy strategies against solid tumors.

DOI: https://doi.org/10.1016/j.ymthe.2024.08.019
J Cell Physiol. 2024 Aug 20. e31416

Nrf2-mediated adenylosuccinate lyase promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma cells through ferroptosis escape.

Tung-Wei Hsu, Wan-Yu Wang, Alvin Chen, Ching-Feng Chiu, Po-Hsiang Liao, Hsin-An Chen, Chih-Ming Su, Shih-Chiang Shen, Kuei-Yen Tsai, Tzu-Hsuan Wang, Yen-Hao Su.

  Pancreatic cancer has one of the highest fatality rates and the poorest prognosis among all cancer types worldwide. Gemcitabine is a commonly used first-line therapeutic drug for pancreatic cancer; however, the rapid development of resistance to gemcitabine treatment has been observed in numerous patients with pancreatic cancer, and this phenomenon limits the survival benefit of gemcitabine. Adenylosuccinate lyase (ADSL) is a crucial enzyme that serves dual functions in de novo purine biosynthesis, and it has been demonstrated to be associated with clinical aggressiveness, prognosis, and worse patient survival for various cancer types. In the present study, we observed significantly lower ADSL levels in gemcitabine-resistant cells (PANC-1/GemR) than in parental PANC-1 cells, and the knockdown of ADSL significantly increased the gemcitabine resistance of parental PANC-1 cells. We further demonstrated that ADSL repressed the expression of CARD-recruited membrane-associated protein 3 (Carma3), which led to increased gemcitabine resistance, and that nuclear factor erythroid 2-related factor 2 (Nrf2) regulated ADSL expression in parental PANC-1 cells. These results indicate that ADSL is a candidate therapeutic target for pancreatic cancer involving gemcitabine resistance and suggest that the Nrf2/ADSL/Carma3 pathway has therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.

Keywords:  Carma3; Nrf2; adenylosuccinate lyase (ADSL); ferroptosis; gemcitabine resistance; pancreatic cancer

DOI:  https://doi.org/10.1002/jcp.31416
Front Oncol. 2024 ;14 1357583

TP53 co-mutations in advanced lung adenocarcinoma: comparative bioinformatic analyses suggest ambivalent character on overall survival alongside KRAS, STK11 and KEAP1 mutations.

Armin Frille, Myriam Boeschen, Hubert Wirtz, Mathias Stiller, Hendrik Bläker, Maximilian von Laffert.

  Background: Recently, we could show that the co-mutations of KRAS + KEAP1, STK11 + KEAP1 and KRAS + STK11 + KEAP1 lead to a significantly shorter median overall survival (mOS) across treatments by analyzing multiple datasets. TP53, a tumor suppressor gene, plays a crucial role in regulating cell cycle progression. Its mutations occur in approximately 40-50% of non-small lung cancer (NSCLC). Co-occurrence of all four mentioned mutations has been a matter of debate for years. The aim of this study was to assess the distribution of these four mutations and the influence of the different co-mutational patterns on survival.Methods: We present a comparative bioinformatic analysis and refer to data of 4,109 patients with lung adenocarcinoma (LUAD).
Results: Most of the mutations within the LUAD belong to TP53-only (29.0%), quadruple-negative (25.9%) and KRAS-only (13.4%). Whereas TP53-mutations seem to have protective effects in the context of further KEAP1- and KRAS + KEAP1-alterations (improved mOS), their role seems contrary if acquired in an already existing combination of mutations as KRAS + STK11, KRAS + STK11 + KEAP1 and STK1 + KEAP1. TP53 co-mutationshad a negative influence on KRAS-only mutated LUAD (mOS reduced significantly by more than 30%).
Discussion: These data underline the need for complex mutational testing to estimate prognosis more accurately in patients with advanced LUAD.

Keywords:  KEAP1; KRAS; NSCLC; STK11; TP53; co-mutations; lung adenocarcinoma; survival

DOI:  https://doi.org/10.3389/fonc.2024.1357583
NPJ Precis Oncol. 2024 Aug 21. 8(1): 183

Targeting Nrf2/PHKG2 axis to enhance radiosensitivity in NSCLC.

Fushi Han, Shuzhen Chen, Kangwei Zhang, Kunming Zhang, Meng Wang, Peijun Wang.

While ferroptosis shows promise in anti-cancer strategy, the molecular mechanisms behind this process remain poorly understood. Our research aims to highlight the regulation of radiotherapy-induced ferroptosis in non-small cell lung cancer (NSCLC) via the NRF2/PHKG2 axis-mediated mechanism. To identify ferroptosis-associated genes associated with radioresistance in NSCLC, this study employed high-throughput transcriptome sequencing and Lasso risk regression analysis. Clinical samples were analyzed to confirm PHKG2 expression changes before and after radiotherapy. The study further examined ferritinophagy-related factors, intracellular iron levels, mitochondrial function, and ferroptosis in NSCLC cells undergoing radiation exposure to explore the effect of PHKG2 on radiosensitivity or radioresistance. The research also demonstrated the transcriptional inhibition of PHKG2 by NRF2 and created in situ transplantation tumor models of NSCLC to examine the role of NRF2/PHKG2 axis in NSCLC radiosensitivity and resistance in vivo. The Lasso risk regression model that incorporated ferroptosis-associated genes effectively predicted the prognosis of patients with NSCLC. Radiotherapy-sensitive tissues exhibited an increased expression of PHKG2. Overexpression of PHKG2 led to elevated intracellular iron levels by promoting ferritinophagy and increased mitochondrial stress-dependent ferroptosis induced by radiotherapy. PHKG2 transcription repression was achieved through NRF2. The FAGs-Lasso risk regression model can accurately predict the prognosis of NSCLC patients. Targeting Nrf2 upregulates the expression of PHKG2 and reverses radiotherapy resistance in NSCLC by promoting iron autophagy and inducing mitochondrial dysfunction, thereby increasing radiotherapy sensitivity.

DOI: https://doi.org/10.1038/s41698-024-00629-3
Int J Biol Macromol. 2024 Aug 19. pii: S0141-8130(24)05649-6. [Epub ahead of print] 134844

Prebiotic stachyose inhibits PRDX5 activity and castration-resistant prostate cancer development.

Rong Wang, Yu Pan, Lan Zhang, Jun Wang, Jiang Ni, Yang Ding, Shaopeng Wang, Jian Yin, Lingwen Ding, Xuebin Ran, Shuangyi Fan, Qiaoyang Sun, Soo Yong Tan, H Phillip Koeffler, Jie Li, Yuanyuan Mi, Yong Q Chen.

  Stachyose (STA) is a prebiotic with poor oral bioavailability. In this study, we developed stachyose caproate (C6-STA), as a novel STA derivative, to demonstrate its high adsorption rate via oral administration. Pharmacokinetic analysis reveals that after absorption, the STA derived from C6-STA reaches its highest peak in the blood, liver, and kidney at 20 min, 30 min, and 12-24 h, with approximate levels of 1200 μg/mL, 0.14 μg/mL, and 0.2-0.3 μg/mL, respectively. In addition, the accumulation of STA in prostate tissues of mice with castration-resistant prostate cancer (CRPC) (1.75 μg/mg) is 10-fold higher than that in normal prostate tissues (0.14 μg/mg). The analysis also reveals that C6-STA has t1/2 of 12.8 h and Tmax of 0.25 h, indicating that it has the potential to be used as a promising drug in clinical practice. The toxicological evaluation shows no obvious side effects of C6-STA in mice administered with a 0.2 g/kg intragastric dose. Pharmacodynamic analysis and mechanism investigation of C6-STA show its ability to inhibit peroxiredoxin 5 (PRDX5) enzyme activity, disrupt PRDX5-nuclear factor erythroid 2-related factor 2 (NRF2) interaction, and decrease NAD(P)H quinone dehydrogenase 1 (NQO1) levels. NQO1 decrease further causes the accumulation of quinone radicals, which ultimately leads to the apoptosis of LNCaP cell-derived drug-tolerant persister (DTP) cells and slows CRPC progression. Our study discovered the anti-tumor activity of stachyose and shows that prebiotics have biological functions in vivo besides in the gut. Further investigation of C6-STA, especially in CRPC patients, is warranted.

Keywords:  Castration-resistant prostate cancer; Drug-tolerant persister; Nuclear factor erythroid 2-related factor 2; Peroxiredoxin 5; Stachyose; Stachyose caproate

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.134844
Int J Oncol. 2024 Oct;pii: 92. [Epub ahead of print]65(4):

Aurantio‑obtusin regulates lipogenesis and ferroptosis of liver cancer cells through inhibiting SCD1 and sensitizing RSL3.

Wen Liu, Jun Deng, Xiao-Jun Tao, Ya Peng, Xiang-Ding Chen, Xiao-Chao Qu, Hong-Wen Deng, Li-Jun Tan.

  Ferroptosis, characterized by iron‑mediated non‑apoptotic cell death and alterations in lipid redox metabolism, has emerged as a critical process implicated in various cellular functions, including cancer. Aurantio‑obtusin (AO), a bioactive compound derived from Cassiae semen (the dried mature seeds of Cassie obtusifolia L. or Cassia toral L.), has anti‑hyperlipidemic and antioxidant properties; however, to the best of our knowledge, the effect of AO on liver cancer cells remains unclear. The Cell Counting Kit‑8, EdU staining and migration assays were employed to assess the anti‑liver cancer activity of AO. Intracellular levels of glutathione peroxidase 4 protein and lipid peroxidation were measured as indicators of ferroptotic status. Immunohistochemical analyses, bioinformatics analyses and western blotting were conducted to evaluate the potential of stearoyl‑CoA desaturase 1 (SCD1) in combination with ferroptosis inducers for the personalized treatment of liver cancer. The present study revealed that AO significantly inhibited the proliferation of liver cancer cells in vitro and in vivo. Mechanistically, AO inhibited AKT/mammalian target of rapamycin (mTOR) signaling, suppressed sterol regulatory element‑binding protein 1 (SREBP1) expression, and downregulated fatty acid synthase expression, thereby inhibiting de novo fatty acid synthesis. Further investigations demonstrated that AO suppressed glutathione peroxidase 4 protein expression through the nuclear factor erythroid 2‑related factor 2/heme oxygenase‑1 pathway, induced ferroptosis in liver cancer cells, and simultaneously inhibited lipogenesis by suppressing SCD1 expression through the AKT/mTOR/SREBP1 pathway. Consequently, this increased the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. Additionally, the enhanced effects of AO and RSL3, which resulted in significant tumor suppression, were confirmed in a xenograft mouse model. In conclusion, the present study demonstrated that AO induced ferroptosis, downregulated the expression of SCD1 and enhanced the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. The synergistic use of AO and a ferroptosis inducer may have promising therapeutic effects in liver cancer cells.

Keywords:  AO; GPX4; SCD1; ferroptosis; liver cancer

DOI:  https://doi.org/10.3892/ijo.2024.5680
J Physiol. 2024 Aug 21.

Muscle-derived IL-1β regulates EcSOD expression via the NBR1-p62-Nrf2 pathway in muscle during cancer cachexia.

Mami Yamada, Eiji Warabi, Hisashi Oishi, Vitor A Lira, Mitsuharu Okutsu.

  Oxidative stress contributes to the loss of skeletal muscle mass and function in cancer cachexia. However, this outcome may be mitigated by an improved endogenous antioxidant defence system. Here, using the well-established oxidative stress-inducing muscle atrophy model of Lewis lung carcinoma (LLC) in 13-week-old male C57BL/6J mice, we demonstrate that extracellular superoxide dismutase (EcSOD) levels increase in the cachexia-prone extensor digitorum longus muscle. LLC transplantation significantly increased interleukin-1β (IL-1β) expression and release from extensor digitorum longus muscle fibres. Moreover, IL-1β treatment of C2C12 myotubes increased NBR1, p62 phosphorylation at Ser351, Nrf2 nuclear translocation and EcSOD protein expression. Additional studies in vivo indicated that intramuscular IL-1β injection is sufficient to stimulate EcSOD expression, which is prevented by muscle-specific knockout of p62 and Nrf2 (i.e. in p62 skmKO and Nrf2 skmKO mice, respectively). Finally, since an increase in circulating IL-1β may lead to unwanted outcomes, we demonstrate that targeting this pathway at p62 is sufficient to drive muscle EcSOD expression in an Nrf2-dependent manner. In summary, cancer cachexia increases EcSOD expression in extensor digitorum longus muscle via muscle-derived IL-1β-induced upregulation of p62 phosphorylation and Nrf2 activation. These findings provide further mechanistic evidence for the therapeutic potential of p62 and Nrf2 to mitigate cancer cachexia-induced muscle atrophy. KEY POINTS: Oxidative stress plays an important role in muscle atrophy during cancer cachexia. EcSOD, which mitigates muscle loss during oxidative stress, is upregulated in 13-week-old male C57BL/6J mice of extensor digitorum longus muscles during cancer cachexia. Using mouse and cellular models, we demonstrate that cancer cachexia promotes muscle EcSOD protein expression via muscle-derived IL-1β-dependent stimulation of the NBR1-p62-Nrf2 signalling pathway. These results provide further evidence for the potential therapeutic targeting of the NBR1-p62-Nrf2 signalling pathway downstream of IL-1β to mitigate cancer cachexia-induced muscle atrophy.

Keywords:  NBR1; Nrf2; SQSTM1/p62; extracellular superoxide dismutase; interleukin‐1β; muscle atrophy; skeletal muscle

DOI:  https://doi.org/10.1113/JP286460