bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2023–01–08
six papers selected by
Caner Geyik, Istinye University
  1. Anesthetic propofol inhibits ferroptosis and aggravates distant cancer metastasis via Nrf2 upregulation.
  2. Stanniocalcin1 knockdown induces ferroptosis and suppresses glycolysis in prostate cancer via the Nrf2 pathway.
  3. Multiple targets of Nrf 2 inhibitor; trigonelline in combating urethane-induced lung cancer by caspase-executioner apoptosis, cGMP and limitation of cyclin D1 and Bcl2.
  4. YAP-activated SATB2 is a coactivator of NRF2 that amplifies anti-oxidative capacity and promotes tumor progression in renal cell carcinoma.
  5. Investigating the functional role of SETD6 in lung adenocarcinoma.
  6. Anti-tumor effects of Auraptene through induction of apoptosis and oxidative stress in a mouse model of colorectal cancer.
  1. Free Radic Biol Med. 2022 Dec 28. pii: S0891-5849(22)01118-2. [Epub ahead of print]
    Anesthetic propofol inhibits ferroptosis and aggravates distant cancer metastasis via Nrf2 upregulation.
    Bo Zhang, Qi Hou, Xiaoli Zhang, Yiming Ma, Junhu Yuan, Shuai Li, Xinhua Zhao, Li Sun, Hongying Wang, Hui Zheng.
      The impact of anesthetic management on the prognosis of patients with cancer undergoing surgery is controversial. Circulating tumor cells (CTCs) play critical roles during cancer metastasis and can be released in large quantities during surgery. The ferroptosis of CTCs is related to metastasis. Whether anesthetics affect distant metastasis by increasing the survival of CTCs is unknown. To test this hypothesis, mice were inoculated with cancer cells via tail vein injection before treatment with propofol or sevoflurane for 2 h. After 2 weeks, more metastases were observed in the propofol group compared with the sevoflurane and vehicle groups. Then, we used the ferroptosis inhibitor ferrostatin-1 to explore the effect of ferroptosis on metastasis. Similar to propofol, pretreatment with ferrostatin-1 significantly increased CTC survival in mouse lungs at 24 h and the tumor burden at 10 weeks post-inoculation. Moreover, propofol protected cancer cells from RSL3-induced ferroptosis in vitro, as evidenced by decreases in intracellular levels of reactive oxygen species (ROS), lipid peroxide, and ferroptosis markers. Further studies showed that propofol treatment upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target genes, including HO-1, NQO1, and SLC7A11. Finally, the targeted knockdown of Nrf2 abolished the anti-ferroptosis effect of propofol. Collectively, we demonstrated the risk of a specific type of anesthetic, propofol, in promoting cancer cell metastasis through Nrf2-mediated ferroptosis inhibition. These findings may guide the choice of anesthetic for surgical removal of tumors.
    Keywords:  Cancer; Ferroptosis; Metastasis; Nrf2; Propofol
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.12.092
  2. Neoplasma. 2022 Dec;pii: 220626N665. [Epub ahead of print]69(6): 1396-1405
    Stanniocalcin1 knockdown induces ferroptosis and suppresses glycolysis in prostate cancer via the Nrf2 pathway.
    Yuan-Qing Dai, Yao Bai, Jie Gu, Ben-Yi Fan.
      Stanniocalcin1 (STC1) is a secreted glycoprotein, which is highly expressed in prostate cancer cells. However, the biological functions of STC1 in modulating ferroptosis and glycolysis in prostate cancer are still not clear. The viability of PC-3 and DU145 cells was detected by CCK-8 assay. The relative Fe2+ level was detected by an Iron Assay Kit. MDA level was detected by Lipid Peroxidation MDA Assay Kit. Glucose uptake and lactate product were measured by Glycolysis Assay Kit and Lactate Assay Kit. In this study, STC1 was highly expressed in prostate cancer tissue specimens and cells. STC1 knockdown suppressed prostate cancer cell proliferation, and upregulated Fe2+ level, reduced glutathione (GSH) level, downregulated GPX4 and SLC7A11 protein expressions in PC-3 cells and DU145 cells. Besides, STC1 knockdown decreased glucose uptake, lactate product, and ATP level, as well as downregulated glycolysis-related protein HK2 and LDHA protein expressions. In addition, STC1 knockdown repressed the Nrf2/HO-1/NQO1 pathway. Nrf2 pathway activator, Oltipraz, upregulated Nrf2, total NQO1, and HO-1 expressions in PC-3 cells and DU145 cells. Moreover, Nrf2 pathway activator Oltipraz reversed the effect of STC1 knockdown on Fe2+ level and GPX4, SLC7A11, HK2, LDHA protein expressions in PC-3 cells and DU145 cells. Finally, STC1 knockdown restrained the tumor volume, tumor weight, and glycolysis in prostate cancer in vivo. Thus, STC1/Nrf2 pathway is a vital pathway to induce ferroptosis and suppress glycolysis in prostate cancer.
    DOI:  https://doi.org/10.4149/neo_2022_220626N665
  3. Eur Rev Med Pharmacol Sci. 2022 Dec;pii: 30690. [Epub ahead of print]26(24): 9393-9408
    Multiple targets of Nrf 2 inhibitor; trigonelline in combating urethane-induced lung cancer by caspase-executioner apoptosis, cGMP and limitation of cyclin D1 and Bcl2.
    M A Hamzawy, A M Abo-Youssef, M N Malak, M M Khalaf.
      OBJECTIVE: Among other types of cancerous lesions, lung cancer is one of the prevalent causes of death. Trigonelline is a plant alkaloid, a significant constituent in coffee, and has shown health benefits in several disorders. The present study aims to investigate the potential therapeutic role of trigonelline in lung cancer. MATERIALS AND METHODS: Seventy-five BALB/C mice were assigned to five groups and treated for 150 days as follows (1): normal control group; (2) trigonelline only (50 mg/kg/ P.O) daily for the last thirty days; (3) urethane (1.5 g/kg B.w/i.p) at day one and sixty; (4) urethane and carboplatin (15 mg/kg i.p) for the last thirty days; and (5) urethane and trigonelline for the last thirty days. Tumor size was measured while blood and lung were collected for biochemical, western blotting analysis, and histological examinations. RESULTS: Urethane demonstrated significant changes in all biochemical and molecular parameters and histological examinations. In animals pretreated with urethane, trigonelline significantly reduced tumor size and restored Nrf2, NF-кB p65, Bcl-2, Cyclin D1, ICAM-1, and MMP-2, along with improving cGMP and active caspase three and refining histological architectures. CONCLUSIONS: Nrf2 signaling may be a promising therapeutic target for adenocarcinoma protection or management. Due to its multiple therapeutic effects on Nrf2, cyclin D1, NF-кB pathways, and the BAX/Bcl2 axis, trigonelline significantly induced cell cycle arrest and apoptosis.
    Graphical Abstract: https://www.europeanreview.org/wp/wp-content/uploads/Graphical_Abstract-1.jpg.
    DOI:  https://doi.org/10.26355/eurrev_202212_30690
  4. Cancer Res. 2023 Jan 04. pii: CAN-22-1693. [Epub ahead of print]
    YAP-activated SATB2 is a coactivator of NRF2 that amplifies anti-oxidative capacity and promotes tumor progression in renal cell carcinoma.
    Juan Jin, Fen Chen, Wenfang He, Li Zhao, Bo Lin, Danna Zheng, Li Chen, Hongchao He, Qiang He.
      Aberrant epigenetic reprogramming contributes to the progression of renal cell carcinoma (RCC). Elucidation of key regulators of epigenetic reprogramming in RCC could help identify therapeutic vulnerabilities to improve treatment. Here, we report upregulation of the nuclear matrix-associated protein SATB2 in RCC samples, which correlated with poor prognosis. SATB2 inhibition suppressed RCC growth and self-renewal capacities. YAP/TEAD4 activated SATB2 expression and depended on SATB2 to enhance cell proliferation. Transcriptome analysis implicated that SATB2 regulates NRF2 downstream targets to suppress oxidative stress without altering NRF2 levels. Integrated ChIP-seq and ATAC-seq analyses demonstrated that SATB2 coordinated with NRF2 to drive enhancer-promoter interactions, amplifying transcriptional activity. SATB2 recruited SWI/SNF complex subunits, including BRD7 or BRG1, to sustain DNA accessibility. Increased SATB2 triggered chromatin remodeling into configurations that rendered RCC more sensitive to SATB2 deficiency. Moreover, SATB2 ablation promoted the sensitivity of RCC to chemotherapy-induced apoptosis. Lastly, targeting SATB2 or BRD7 effectively restricted the proliferation of YAP-high tumors in patient-derived xenografts and patient-derived organoids. Together, SATB2 is an oncogenic chromatin organizer in RCC, and targeting SATB2 is an effective strategy to suppress the YAP-high RCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1693
  5. BMC Cancer. 2023 Jan 06. 23(1): 18
    Investigating the functional role of SETD6 in lung adenocarcinoma.
    Jing Xu, Hui Zhou, Ziling Luo, Jie Chen, Man Liu.
       BACKGROUND: SET domain containing 6 (SETD6) has been shown to be upregulated in multiple human cancers and can promote malignant cell survival. However, expression and function of SETD6 in lung adenocarcinoma (LUAD) remains unaddressed. This study aimed to demonstrate the expression pattern, biological roles and potential mechanisms by which SETD6 dysregulation is associated with LUAD.
    METHODS: The expression level of SETD6 was evaluated in LUAD clinical specimens and its correlation with clinical parameters were analyzed. In vitro, gain-of-function and loss-of-function experiments were performed to evaluate the effects of SETD6 on cell proliferation, apoptosis, migration, and colony formation of LUAD cell line A549. Western-blot was performed to investigate the involvement of nuclear factor-κB (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways as downstream signaling of SETD6 in LUAD cells.
    RESULTS: Compared with non-tumorous tissues, SETD6 was overexpressed in tumor tissues, and its overexpression significantly correlates with higher rates of regional lymph node metastasis and poor prognosis in patients with LUAD. In A549 cell line, SETD6 overexpression could promote cell proliferation, migration, colony formation and inhibit cell apoptosis, whereas SETD6 knockdown caused the opposite effects. Furthermore, we demonstrated that the mechanisms underlying the effect of SETD6 on LUAD biological behaviors may be through its interaction with NF-κB and Nrf2 signaling pathways.
    CONCLUSIONS: SETD6, which is highly expressed in LUAD tumor tissues, plays an important role in promoting the malignant behaviors of LUAD via likely the NF-κB and Nrf2 signaling pathways.
    Keywords:  Lung adenocarcinoma; Nuclear factor erythroid 2–related factor 2; Nuclear factor-κB; SET domain containing 6
    DOI:  https://doi.org/10.1186/s12885-022-10476-9
  6. Tissue Cell. 2022 Dec 20. pii: S0040-8166(22)00276-2. [Epub ahead of print]81 102004
    Anti-tumor effects of Auraptene through induction of apoptosis and oxidative stress in a mouse model of colorectal cancer.
    Sepideh Ebrahimi, Mohammad Soukhtanloo, Zohreh Mostafavi-Pour.
      The main strategy of cancer cells for survival is uncontrolled cell division and escape from apoptosis. The use of anticancer agents inducing the production of reactive oxygen species (ROS) and controlling cell division might be a therapeutic approach to eradicate cancer cells. Herein, we examined the therapeutic effects of Auraptene on CT26 cells as well as on a mouse model of colorectal cancer (CRC). The spheroid assay was also conducted to analyze the anti-proliferative activity of Auraptene. We also assessed the in vitro analysis of ROS generation. The impact of Auraptene on oxidant/antioxidant markers, as well as the mRNA expression of Bax, Bcl-2, Nrf2, Cyclin D1, and Survivin genes, was evaluated by qPCR in tumor samples. As a result, Auraptene significantly reduced the size of CT26 spheroids at a dose of 200 µM. After 12 h, ROS levels were significantly elevated in CT26 cells. The administration of Auraptene induced apoptosis and the cell cycle arrest by modulating Bax, Bcl-2, Nrf2, Cyclin D1, and Survivin mRNA levels. Furthermore, our results demonstrated that Auraptene suppressed CAT, GSH (reduced Glutathione), and FRAP while increasing MDA in tissue homogenates which in turn could raise oxidative stress and stimulate apoptosis. Therefore, Auraptene may act as a powerful adjuvant therapy in CRC since it triggers apoptosis and cell cycle.
    Keywords:  Anti-tumor effect; Apoptosis; Auraptene; Oxidative stress
    DOI:  https://doi.org/10.1016/j.tice.2022.102004
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