bims-nurfca 2023-09-03 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2023–09–03
nine papers selected by
Caner Geyik, Istinye University

FSP1 confers ferroptosis resistance in KEAP1 mutant non-small cell lung carcinoma in NRF2-dependent and -independent manner.
In vitro siRNA-mediated GPX4 and AKT1 silencing in oxaliplatin resistance cancer cells induces ferroptosis and apoptosis.
Allyl-isothiocyanate against colorectal cancer via the mutual dependent regulation of p21 and Nrf2.
Nrf2 inhibition increases sensitivity to chemotherapy of colorectal cancer by promoting ferroptosis and pyroptosis.
USP8 promotes gemcitabine resistance of pancreatic cancer via deubiquitinating and stabilizing Nrf2.
Impact of albumin-lymphocyte-platelet-c-reactive protein index as a prognostic indicator of hepatocellular carcinoma after resection: Associated with nuclear factor erythroid 2-related factor 2.
Perillaldehyde Mitigates Ionizing Radiation-Induced Intestinal Injury by Inhibiting Ferroptosis via the Nrf2 Signaling Pathway.
Nrf2 Signaling Pathway: a Potential Therapeutic Target in Combating Oxidative Stress and Neurotoxicity in Chemotherapy-Induced Cognitive Impairment.
Galangin attenuates doxorubicin-induced cardiotoxicity via activating nuclear factor erythroid 2-related factor 2/heme oxygenase 1 signaling pathway to suppress oxidative stress and inflammation.

Cell Death Dis. 2023 08 26. 14(8): 567

FSP1 confers ferroptosis resistance in KEAP1 mutant non-small cell lung carcinoma in NRF2-dependent and -independent manner.

Jong Woo Kim, Min-Ju Kim, Tae-Hee Han, Ji-Yoon Lee, Sangok Kim, Hyerin Kim, Kyoung-Jin Oh, Won Kon Kim, Baek-Soo Han, Kwang-Hee Bae, Hyun Seung Ban, Soo Han Bae, Sang Chul Lee, Haeseung Lee, Eun-Woo Lee.

Ferroptosis, a type of cell death induced by lipid peroxidation, has emerged as a novel anti-cancer strategy. Cancer cells frequently acquire resistance to ferroptosis. However, the underlying mechanisms are poorly understood. To address this issue, we conducted a thorough investigation of the genomic and transcriptomic data derived from hundreds of human cancer cell lines and primary tissue samples, with a particular focus on non-small cell lung carcinoma (NSCLC). It was observed that mutations in Kelch-like ECH-associated protein 1 (KEAP1) and subsequent nuclear factor erythroid 2-related factor 2 (NRF2, also known as NFE2L2) activation are strongly associated with ferroptosis resistance in NSCLC. Additionally, AIFM2 gene, which encodes ferroptosis suppressor protein 1 (FSP1), was identified as the gene most significantly correlated with ferroptosis resistance, followed by multiple NRF2 targets. We found that inhibition of NRF2 alone was not sufficient to reduce FSP1 protein levels and promote ferroptosis, whereas FSP1 inhibition effectively sensitized KEAP1-mutant NSCLC cells to ferroptosis. Furthermore, we found that combined inhibition of FSP1 and NRF2 induced ferroptosis more intensely. Our findings imply that FSP1 is a crucial suppressor of ferroptosis whose expression is partially dependent on NRF2 and that synergistically targeting both FSP1 and NRF2 may be a promising strategy for overcoming ferroptosis resistance in cancer.

DOI: https://doi.org/10.1038/s41419-023-06070-x
Med Oncol. 2023 Aug 26. 40(10): 279

In vitro siRNA-mediated GPX4 and AKT1 silencing in oxaliplatin resistance cancer cells induces ferroptosis and apoptosis.

Morteza Golbashirzadeh, Hamid Reza Heidari, Ali Asghar Aghamolayi, Yasin Fattahi, Mehdi Talebi, Ahmad Yari Khosroushahi.

  Oxaliplatin is a member of platinum-based chemotherapy drugs frequently used in colorectal cancer (CRC). However, resistance to oxaliplatin causes tumor progression and metastasis. Akt1 and Gpx4 are essential regulator genes of apoptosis and ferroptosis pathways. Inhibition of these genes might eradicate oxaliplatin resistance in resistant CRC cells. We compared two cell death strategies to reverse drug resistance in Caco-2 and HT-29 oxaliplatin-resistant cell lines. We used the AKT1-specific siRNA to induce apoptosis. Also, GPX4-specific siRNA and FIN56 were utilized to generate ferroptosis. The effect of these treatments was assessed by reactive oxygen species (ROS) formation, cell viability, and protein expression level assays. Besides, the expression of GPX4, CoQ10, and NRF2 was assessed in both cell lines after treatments. Correctly measuring the expression of these responsible genes and proteins confirms the occurrence of different types of cell death. In addition, the ability of Akt1/ GPX4 siRNA in resensitizing HT-29 and Caco-2 oxaliplatin resistance cells was evaluated. Our finding showed that the upregulation of GPX4/siRNA caused a reduction in GPX4 and CoQ10 expressions in both cell lines. However, the expression level of NRF2 showed the same level in our cell lines, so we observed a downregulation of NRF2 in resistant CRC cell lines. Cell viability assay indicated that induction of ferroptosis by GPX4/siRNA or FIN56 and apoptosis by Akt1/siRNA in resistant cell lines could reverse the oxaliplatin resistance. We concluded that downregulation of Akt1 or Gpx4 could increase the efficacy of oxaliplatin to overcome the resistance compared to FIN56.

Keywords:  Ferroptosis; Gpx4; Nrf2; Oxaliplatin; ROS; Resistance; siRNA

DOI:  https://doi.org/10.1007/s12032-023-02130-6
Eur J Pharmacol. 2023 Aug 25. pii: S0014-2999(23)00528-9. [Epub ahead of print] 176016

Allyl-isothiocyanate against colorectal cancer via the mutual dependent regulation of p21 and Nrf2.

Xiaoyan Ren, Gaoshan Zhang, Xiang Ling, Linhua Zhang, Yangyang Tian, Guoxiang Zhu, Pengbo Wang, Jianmei W Leavenworth, Lin Luo, Fengzhi Li.

  Allyl-isothiocyanate (AITC) is a common Isothiocyanates (ITC) and its chemo-preventive and anti-tumor effects are believed to be related to the activation of NF-E2 p45-related Factor 2 (Nrf2). However, its anti-tumor effects on colorectal cancer (CRC) are not well elucidated. Here, we investigated the therapeutic in vitro and/or in vivo effects and mechanisms of action (MOA) for AITC on CRC cell line HCT116 (human) and MC38 (mouse). AITC treatment in a low concentration range (1 mg/kg in vivo) significantly inhibited the tumor cell growth and increased the expression of p21 and Nrf2. The AITC-mediated induction of p21 was dependent on Nrf2 but independent on p53 in vitro and in vivo at low dose. In contrast, the high dose of AITC (5 mg/kg in vivo) failed to increase substantial levels of p21/MdmX, and impaired the total antioxidant capacity of tumors and subsequent anti-tumor effect in vivo. These results suggest that an optimal dose of AITC is important and required for the proper Nrf2 activation and its anti-CRC effects and thus, providing insights into the potential applications of AITC for the prevention and treatment of CRC.

Keywords:  Allyl-isothiocyanate (AITC); Colorectal cancer (CRC); Murine double minute X (MdmX); NF-E2 p45-related factor 2 (Nrf2); p21

DOI:  https://doi.org/10.1016/j.ejphar.2023.176016
Sci Rep. 2023 Sep 01. 13(1): 14359

Nrf2 inhibition increases sensitivity to chemotherapy of colorectal cancer by promoting ferroptosis and pyroptosis.

Yongzhou Huang, Wenchang Yang, Lei Yang, Tao Wang, Chengguo Li, Jiaxian Yu, Peng Zhang, Yuping Yin, Ruidong Li, Kaixiong Tao.

Oxaliplatin is widely used in chemotherapy for colorectal cancer (CRC), but its sensitivity has become a major obstacle to limiting efficacy. Many literatures reported that Nrf2 activation promoted tumor chemoresistance. In this study, we explored the role and mechanism of Nrf2 inhibition in oxaliplatin-based chemosensitivity of CRC. In vitro experiments, we applied 4-octyl itaconate (4-OI) to activate Nrf2, and used lentivirus to knock down Nrf2 in CRC cell lines. By measuring cell viability, colony formation, apoptosis, reactive oxygen species production, and western blot, we found that oxaliplatin and lobaplatin suppressed the growth of HCT-116 and LOVO cells in a dose-dependent manner, and promoted the expression of Nrf2. 4-OI, an Nrf2 activator, reduced the sensibility of CRC cells to oxaliplatin and lobaplatin, while the knockdown of Nrf2 promoted the sensibility of CRC cells to oxaliplatin and lobaplatin. Through the public databases, we found that the expression of GPX4 in normal tissues was lower compared with cancer tissues in CRC, and the high GPX4 expression predicted a poor prognosis. Meanwhile, we found that oxaliplatin reduced the expression of GPX4 in vitro. The knockdown of Nrf2 enhanced the effects of oxaliplatin to reduce the expression of GPX4 and GSH content, and increase the MDA content, which enhanced oxaliplatin-induced ferroptosis. Subsequently, we found that oxaliplatin promoted the expression of GSDME-N, and induced LDH, IL-1β, and TNF-a release, and the knockdown of Nrf2 aggravated the occurrence of GSMDE-mediated pyroptosis. Finally, we found that the knockdown of Nrf2 enhanced the inhibition of oxaliplatin on HCT116 xenograft tumor growth in vivo. Thus, our study showed that Nrf2 inhibition improved sensitivity to oxaliplatin of CRC cells by promoting ferroptosis and pyroptosis, which provided a new target for overcoming chemoresistance in CRC.

DOI: https://doi.org/10.1038/s41598-023-41490-x
Biomed Pharmacother. 2023 Aug 26. pii: S0753-3322(23)01150-2. [Epub ahead of print]166 115359

USP8 promotes gemcitabine resistance of pancreatic cancer via deubiquitinating and stabilizing Nrf2.

Jing Cui, Yao Guo, Tao Yin, Shanmiao Gou, Jiongxin Xiong, Xueyi Liang, Chong Lu, Tao Peng.

  Gemcitabine (Gem) is the first-line chemotherapy drug for pancreatic cancer, but the acquired chemoresistance also hinders its application. Therefore, research about Gem resistance plays a crucial role in enhancing the therapeutic effect of Gem. As a deubiquitinating enzyme, ubiquitin-specific protease 8 (USP8) was shown to play vital roles in the tumorigenesis processes of several cancers; however, the effect of USP8 on Gem resistance of pancreatic cancer still remains largely unknown. In the current study, we observed that the expression of USP8 was increased in pancreatic cancer patients, it is related to the recurrence of Gem chemotherapy, and USP8 expression could be induced by Gem application. Furthermore, USP8 was found to promote Gem resistance both in vivo and in vitro via regulating cell viability and apoptosis. Moreover, USP8 enhanced the activation of Nrf2 signaling which is dependent on its deubiquitinase ability. At last, we illustrated that USP8 interacted with Nrf2 directly and deubiquitinated K48-linked polyubiquitin chains from Nrf2, stabilizing the expression of Nrf2. In summary, the manuscript revealed the role of USP8 in Gem chemoresistance and suggested USP8 as a potential therapeutic target for pancreatic cancer.

Keywords:  Chemoresistance; Gemcitabine; Nrf2; Pancreatic cancer; USP8

DOI:  https://doi.org/10.1016/j.biopha.2023.115359
Hepatol Res. 2023 Aug 26.

Impact of albumin-lymphocyte-platelet-c-reactive protein index as a prognostic indicator of hepatocellular carcinoma after resection: Associated with nuclear factor erythroid 2-related factor 2.

Norifumi Iseda, Shinji Itoh, Katsuya Toshida, Yuuki Nakayama, Takuma Ishikawa, Yuriko Tsutsui, Takuma Izumi, Yuki Bekki, Shohei Yoshiya, Takeo Toshima, Tomoharu Yoshizumi.

   AIM: To investigate the prognostic value of preoperative albumin-lymphocyte-platelet-c-reactive protein (ALPC) index in patients with hepatocellular carcinoma (HCC) undergoing curative hepatectomy. We also evaluated with the relationship of the ALPC index and phosphorylated nuclear factor erythroid 2-related factor 2 (p-Nrf2) levels.
METHODS: Data were analyzed retrospectively from 256 patients who underwent resection for HCC. For cross-validation, patients were divided into the training and testing cohort. We assessed eight combinations of inflammatory markers for predictive value for recurrence. We examined the associations of the ALPC index with recurrence-free survival (RFS) and overall survival (OS) in univariate and multivariate analyses (Cox proportional hazards model). Immunohistochemical staining of p-Nrf2 was performed on tumor samples of 317 patients who underwent hepatic resection for HCC.
RESULTS: High preoperative ALPC index correlated with a high serum albumin concentration, small tumor size, a low rate of poor differentiation, solitary tumor, early Barcelona Clinic Liver Cancer stage and a low rate of microscopic intrahepatic metastasis in the training dataset. High preoperative ALPC index correlated with a high serum albumin concentration, high serum alpha-fetoprotein concentration, small tumor size, a low rate of poor differentiation and a low rate of microscopic intrahepatic metastasis in the testing dataset. Higher preoperative ALPC index was an independent predictor of longer RFS and OS in the training and testing datasets. High ALPC index was associated with negative p-Nrf2 expression in HCC tumor cells.
CONCLUSIONS: We showed that a high ALPC index was an independent prognostic factor for HCC patients undergoing curative hepatic resection. This article is protected by copyright. All rights reserved.

Keywords:  albumin-lymphocyte-platelet-c-reactive protein index; hepatocellular carcinoma; prognosis

DOI:  https://doi.org/10.1111/hepr.13958
Mol Nutr Food Res. 2023 Sep 01. e2300232

Perillaldehyde Mitigates Ionizing Radiation-Induced Intestinal Injury by Inhibiting Ferroptosis via the Nrf2 Signaling Pathway.

Lin-Feng Tang, Xiaoming Ma, Li-Wei Xie, Hao Zhou, Jiahua Yu, Zhen-Xin Wang, Ming Li.

   SCOPE: Gastrointestinal toxicity is one of the major side effects of abdominopelvic tumor radiotherapy. Studies have shown that perillaldehyde (PAH) has antioxidant, antiinflammatory, antimicrobial activity, and antitumor effects. This study aims to determine whether PAH has radioprotective effects on radiation-induced intestinal injury and explore the underlying mechanisms.
METHODS AND RESULTS: C57BL/6J mice are gavaged with PAH for 7 days, then exposed to a single dose of 13 Gy X-ray total abdominal irradiation (TAI). PAH treatment prolongs the survival time, promotes the survival of crypt cells, attenuates radiation-induced DNA damage, and mitigates intestinal barrier damage in the irradiated mice. PAH also shows radioprotective effects in intestinal crypt organoids and human intestinal epithelial cells (HIEC-6). PAH-mediated radioprotection is associated with the upregulation of nuclear factor erythroid-2 related factor 2 (Nrf2), activation of the antioxidant pathway, and inhibition of ferroptosis. Notably, treatment with the Nrf2 inhibitor ML385 abolishes the protective effects of PAH, indicating that Nrf2 activation is essential for PAH activity.
CONCLUSION: PAH inhibits ionizing radiation (IR)-induced ferroptosis and attenuates intestinal injury after irradiation by activating Nrf2 signaling. Therefore, PAH is a promising therapeutic strategy for IR-induced intestinal injury.

Keywords:  ferroptosis; nuclear factor erythroid-2 related factor 2; perillaldehyde; radiation-induced intestinal injury; reactive oxygen species

DOI:  https://doi.org/10.1002/mnfr.202300232
Mol Neurobiol. 2023 Aug 29.

Nrf2 Signaling Pathway: a Potential Therapeutic Target in Combating Oxidative Stress and Neurotoxicity in Chemotherapy-Induced Cognitive Impairment.

Roshan Lal, Ravinder Naik Dharavath, Kanwaljit Chopra.

  Chemotherapy-induced cognitive impairment (CICI) is one of the major adverse effects of antineoplastic drugs, which decrease the quality of life in cancer survivors. Extensive experimental and clinical research suggests that chemotherapeutic drugs generate an enormous amount of reactive oxygen species (ROS), contributing to oxidative stress, neuroinflammation, blood-brain barrier (BBB) disruption, and neuronal death, eventually leading to CICI. Despite the progress in exploring different pathological mechanisms of CICI, effective treatment to prevent CICI progression has not been developed yet. Nrf2 is the principal transcription factor that regulates cellular redox balance and inflammation-related gene expression. Emerging evidence suggests that upregulation of Nrf2 and its target genes could suppress oxidative stress, and neuroinflammation, restore BBB integrity, and increase neurogenesis. This review discusses the role of Nrf2 in CICI, how it responds to oxidative stress, inflammation, neurotoxicity, and potential Nrf2 activators that could be used to enhance Nrf2 activation in CICI.

Keywords:  BDNF; Blood-brain barrier; Memory impairment; Neuroinflammation; Reactive oxygen species

DOI:  https://doi.org/10.1007/s12035-023-03559-6
Phytother Res. 2023 Sep 01.

Galangin attenuates doxorubicin-induced cardiotoxicity via activating nuclear factor erythroid 2-related factor 2/heme oxygenase 1 signaling pathway to suppress oxidative stress and inflammation.

Guangyao Fang, Xiuchuan Li, Fengyuan Yang, Ting Huang, Chenming Qiu, Ke Peng, Yongjian Yang, Cong Lan.

  Doxorubicin (DOX) has aroused contradiction between its potent anti-tumor capacity and severe cardiotoxicity. Galangin (Gal) possesses antioxidant, anti-inflammatory, and antiapoptotic activities. We aimed to explore the role and underlying mechanisms of Gal on DOX-induced cardiotoxicity. Mice were intraperitoneally injected with DOX (3 mg/kg, every 2 days for 2 weeks) to generate cardiotoxicity model and Gal (15 mg/kg, 2 weeks) was co-administered via gavage daily. Nuclear factor erythroid 2-related factor 2 (Nrf2) specific inhibitor, ML385, was employed to explore the underlying mechanisms. Compared to DOX-insulted mice, Gal effectively improved cardiac dysfunction and ameliorated myocardial damage. DOX-induced increase of reactive oxygen species, malondialdehyde, and NADPH oxidase activity and downregulation of superoxide dismutase (SOD) activity were blunted by Gal. Gal also markedly blocked increase of IL-1β, IL-6, and TNF-α in DOX-insulted heart. Mechanistically, Gal reversed DOX-induced downregulation of Nrf2, HO-1, and promoted nuclear translocation of Nrf2. ML385 markedly blunted the cardioprotective effects of Gal, as well as inhibitive effects on oxidative stress and inflammation. Gal ameliorates DOX-induced cardiotoxicity by suppressing oxidative stress and inflammation via activating Nrf2/HO-1 signaling pathway. Gal may serve as a promising cardioprotective agent for DOX-induced cardiotoxicity.

Keywords:  Galangin; Nrf2/HO-1 signaling pathway; cardiomyocyte apoptosis; doxorubicin-induced cardiotoxicity; inflammation; oxidative stress

DOI:  https://doi.org/10.1002/ptr.7991