bims-nurfca 2024-01-21 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2024–01–21
sixteen papers selected by
Caner Geyik, Istinye University

Genome-wide analyses reveal the contribution of somatic variants to the immune landscape of multiple cancer types.
Triptolide inhibits proliferation and invasion of colorectal cancer cells by blocking Nrf2 expression.
A novel crosstalk between Nrf2 and Smad2/3 bridged by two nuanced Keap1 isoforms with their divergent effects on these distinct family transcription factors.
Inhibition of NRF2 enhances the acute myeloid leukemia cell death induced by venetoclax via the ferroptosis pathway.
Ameliorative inhibition of sirtuin 6 by imidazole derivative triggers oxidative stress-mediated apoptosis associated with Nrf2/Keap1 signaling in non-small cell lung cancer cell lines.
The effect of p53 on the activity of NRF2 and NDRG2 genes through apoptotic pathway in IDH-wildtype glioblastoma.
Thiol starvation triggers melanoma state switching in an ATF4 and NRF2-dependent manner.
PSMD12 promotes non-small cell lung cancer progression through activating the Nrf2/TrxR1 pathway.
APOC1 reduced anti-PD-1 immunotherapy of nonsmall cell lung cancer via the transformation of M2 into M1 macrophages by ferroptosis by NRF2/HO-1.
Exploring the multifaceted role of NRF2 in brain physiology and cancer: A comprehensive review.
Piperlongumine inhibits esophageal squamous cell carcinoma in vitro and in vivo by triggering NRF2/ROS/TXNIP/NLRP3-dependent pyroptosis.
Novel Sulforaphane Analog Disrupts Phosphatidylinositol-3-Kinase-Protein Kinase B Pathway and Inhibits Cancer Cell Progression via Reactive Oxygen Species-Mediated Caspase-Independent Apoptosis.
Uncovering immune checkpoint heterogeneity in oral squamous cell carcinoma using single cell RNA-sequencing data highlights three subgroups of patients with distinct immune phenotypes.
Glucocorticoid receptor mediated sensitization of colon cancer to photodynamic therapy induced cell death.
Retracted: MCU That Is Transcriptionally Regulated by Nrf2 Augments Malignant Biological Behaviors in Oral Squamous Cell Carcinoma Cells.
Retracted: The Impact of Catalpol on Proliferation, Apoptosis, Migration, and Oxidative Stress of Lung Cancer Cells Based on Nrf2/ARE Signaling.

PLoS Genet. 2024 Jan 19. 20(1): e1011134

Genome-wide analyses reveal the contribution of somatic variants to the immune landscape of multiple cancer types.

Wenjian Bi, Zhiyu Xu, Feng Liu, Zhi Xie, Hao Liu, Xiaotian Zhu, Wenge Zhong, Peipei Zhang, Xing Tang.

It has been well established that cancer cells can evade immune surveillance by mutating themselves. Understanding genetic alterations in cancer cells that contribute to immune regulation could lead to better immunotherapy patient stratification and identification of novel immune-oncology (IO) targets. In this report, we describe our effort of genome-wide association analyses across 22 TCGA cancer types to explore the associations between genetic alterations in cancer cells and 76 immune traits. Results showed that the tumor microenvironment (TME) is shaped by different gene mutations in different cancer types. Out of the key genes that drive multiple immune traits, top hit KEAP1 in lung adenocarcinoma (LUAD) was selected for validation. It was found that KEAP1 mutations can explain more than 10% of the variance for multiple immune traits in LUAD. Using public scRNA-seq data, further analysis confirmed that KEAP1 mutations activate the NRF2 pathway and promote a suppressive TME. The activation of the NRF2 pathway is negatively correlated with lower T cell infiltration and higher T cell exhaustion. Meanwhile, several immune check point genes, such as CD274 (PD-L1), are highly expressed in NRF2-activated cancer cells. By integrating multiple RNA-seq data, a NRF2 gene signature was curated, which predicts anti-PD1 therapy response better than CD274 gene alone in a mixed cohort of different subtypes of non-small cell lung cancer (NSCLC) including LUAD, highlighting the important role of KEAP1-NRF2 axis in shaping the TME in NSCLC. Finally, a list of overexpressed ligands in NRF2 pathway activated cancer cells were identified and could potentially be targeted for TME remodeling in LUAD.

DOI: https://doi.org/10.1371/journal.pgen.1011134
Chem Biol Drug Des. 2024 Jan;103(1): e14410

Triptolide inhibits proliferation and invasion of colorectal cancer cells by blocking Nrf2 expression.

Hui-Feng Wang, Zhi-Long Zhao.

  Triptolide (TPL), the main active ingredient of Tripterygium wilfordii, has anti-inflammatory, immunomodulatory, and antitumor actions. It can also inhibit cell proliferation and metastasis while promoting apoptosis of several tumors, such as colorectal cancer (CRC). However, the mechanism of TPL against CRC is not clear. This study was designed to investigate the effects and molecular mechanisms of TPL on the proliferation and invasion ability of CRC cells. A human CRC cell line (HT29 cell line) cultured in vitro was treated with different concentrations of TPL (0, 25, 50, and 100 nmol/L). The proliferation of cells was detected by MTT, the invasion ability of cells by Transwell, and the apoptosis level by flow cytometry. The protein expression levels of nuclear factor-erythroid 2-related factor 2 (Nrf2), matrix metalloproteinase (MMP)-2, and MMP-9 were detected by western blotting. After transfection with sh-Nrf2, HT29 cells were divided into NC group, NC + TPL group and sh-Nrf2 + TPL group, and the above assays were repeated for each group. TPL significantly inhibited the proliferation and invasion ability of HT29 cells and promoted apoptosis (p < .05). Notably, its inhibitory or promotional effects were concentration-dependent, which were enhanced with increasing drug concentration (p < .05). After silencing Nrf2 expression, the proliferation, and invasion ability of HT29 cells were further significantly inhibited while cells apoptosis was further promoted (p < .05). Besides, the decreased Nrf2 expression reduced the protein expression levels of MMP-2 and MMP-9 (p < .05). TPL can effectively inhibit the proliferation and invasion while promoting apoptosis of HT29 cells. And its mechanism of action may be related to the inhibition of Nrf2 signaling expression.

Keywords:  Nrf2 signaling; apoptosis; colorectal cancer (CRC); invasion ability; triptolide (TPL)

DOI:  https://doi.org/10.1111/cbdd.14410
Free Radic Biol Med. 2024 Jan 17. pii: S0891-5849(24)00025-X. [Epub ahead of print]

A novel crosstalk between Nrf2 and Smad2/3 bridged by two nuanced Keap1 isoforms with their divergent effects on these distinct family transcription factors.

Feilong Chen, Qing Wang, Mei Xiao, Deshuai Lou, Reziyamu Wufur, Shaofan Hu, Zhengwen Zhang, Yeqi Wang, Yiguo Zhang.

  The Keap1-Nrf2 signalling to transcriptionally regulate antioxidant response element (ARE)-driven target genes has been accepted as key redox-sensitive pathway governing a vast variety of cellular stresses during healthy survival and disease development. Herein, we identified two nuanced isoforms α and β of Keap1 in HepG2 cells, arising from its first and another in-frame translation starting codons, respectively. In identifying those differential expression genes monitored by Keap1α and/or Keap1β, an unusual interaction of Keap1 with Smad2/3 was discovered by parsing transcriptome sequencing, Keap1-interacting protein profiling and relevant immunoprecipitation data. Further examination validated that Smad2/3 enable physical interaction with Keap1, as well as its isoforms α and β, by both EDGETSD and DLG motifs in the linker regions between their MH1 and MH2 domains, such that the stability of Smad2/3 and its transcriptional activity are enhanced with their prolonged half-lives and relevant signalling responses from the cytoplasmic to nuclear compartments. The activation of Smad2/3 by Keap1, Keap1α or Keap1β was much likely contributable to a coordinative or another competitive effect of Nrf2, particularly in distinct Keap1-based cellular responses to its cognate growth factor (i.e. TGF-β1) or redox stress (e.g. stimulated by tBHQ and DTT). Overall, this discovery presents a novel functional bridge crossing the Keap1-Nrf2 redox signalling and the TGF-β1-Smad2/3 pathways so as to coordinately regulate the healthy growth and development.

Keywords:  Keap1; Keap1α; Keap1β; Nrf2; Protein-protein interaction; Smad2; Smad3; Transcriptional regulation

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.025
Cell Death Discov. 2024 Jan 18. 10(1): 35

Inhibition of NRF2 enhances the acute myeloid leukemia cell death induced by venetoclax via the ferroptosis pathway.

Xibao Yu, Yan Wang, Jiaxiong Tan, Yuchen Li, Pengyue Yang, Xuan Liu, Jing Lai, Yue Zhang, Letong Cai, Yinfeng Gu, Ling Xu, Yangqiu Li.

Venetoclax, an inhibitor that selectively targets B cell lymphoma-2 (BCL-2) that has been approved for treating adult acute myeloid leukemia (AML) in combination with hypomethylating agents. However, its short duration of response and emergence of resistance are significant issues. In this study, we found that the sensitivity of AML cells to venetoclax was considerably enhanced by ML385, an inhibitor of the ferroptosis factor nuclear transcription factor erythroid 2-related factor 2 (NRF2). Using AML samples, we verified that NRF2 and its target gene ferritin heavy chain 1 (FTH1) were highly expressed in patients with AML and correlated with poor prognosis. Downregulation of NRF2 could inhibit FTH1 expression and significantly enhance the venetoclax-induced labile iron pool and lipid peroxidation. By contrast, NRF2 overexpression or administration of the reactive oxygen species inhibitor N-acetylcysteine and vitamin E could effectively suppress the anti-AML effects of ML385+venetoclax. Furthermore, the ferroptosis inducer erastin increased the anti-AML effects of venetoclax. Our study demonstrated that NRF2 inhibition could enhance the AML cell death induced by venetoclax via the ferroptosis pathway. Thus, the combination of ML385 with venetoclax may offer a favorable strategy for AML treatment.

DOI: https://doi.org/10.1038/s41420-024-01800-2
Front Pharmacol. 2023 ;14 1335305

Ameliorative inhibition of sirtuin 6 by imidazole derivative triggers oxidative stress-mediated apoptosis associated with Nrf2/Keap1 signaling in non-small cell lung cancer cell lines.

Uma Maheswara Rao Dindi, Sameer Al-Ghamdi, Naif Abdurhman Alrudian, Salman Bin Dayel, Abdulwahab Ali Abuderman, Mohammed Saad Alqahtani, Nasraddin Othman Bahakim, Thiyagarajan Ramesh, Ravikumar Vilwanathan.

  Background: Redox homeostasis is the vital regulatory system with respect to antioxidative response and detoxification. The imbalance of redox homeostasis causes oxidative stress. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2, also called Nfe2l2)/Kelchlike ECH-associated protein 1 (Keap1) signaling is the major regulator of redox homeostasis. Nrf2/Keap1 signaling is reported to be involved in cancer cell growth and survival. A high level of Nrf2 in cancers is associated with poor prognosis, resistance to therapeutics, and rapid proliferation, framing Nrf2 as an interesting target in cancer biology. Sirtuins (SIRT1-7) are class III histone deacetylases with NAD + dependent deacetylase activity that have a remarkable impact on antioxidant and redox signaling (ARS) linked with Nrf2 deacetylation thereby increasing its transcription by epigenetic modifications which has been identified as a crucial event in cancer progression under the influence of oxidative stress in various transformed cells. SIRT6 plays an important role in the cytoprotective effect of multiple diseases, including cancer. This study aimed to inhibit SIRT6 using an imidazole derivative, Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl] acetate, to assess its impact on Nrf2/Keap1 signaling in A549 and NCI-H460 cell lines. Method: Half maximal inhibitory concentration (IC50) of Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl] acetate was fixed by cell viability assay. The changes in the gene expression of important regulators involved in this study were examined using quantitative real-time PCR (qRT-PCR) and protein expression changes were confirmed by Western blotting. The changes in the antioxidant molecules are determined by biochemical assays. Further, morphological studies were performed to observe the generation of reactive oxygen species, mitochondrial damage, and apoptosis. Results: We inhibited SIRT6 using Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl] acetate and demonstrated that SIRT6 inhibition impacts the modulation of antioxidant and redox signaling. The level of antioxidant enzymes and percentage of reactive oxygen species scavenging activity were depleted. The morphological studies showed ROS generation, mitochondrial damage, nuclear damage, and apoptosis. The molecular examination of apoptotic factors confirmed apoptotic cell death. Further, molecular studies confirmed the changes in Nrf2 and Keap1 expression during SIRT6 inhibition. Conclusion: The overall study suggests that SIRT6 inhibition by imidazole derivative disrupts Nrf2/Keap1 signaling leading to oxidative stress and apoptosis induction.

Keywords:  Epigenetics; HDAC; HDACi; KEAP1; Nrf2; SIRT6

DOI:  https://doi.org/10.3389/fphar.2023.1335305
Pathol Res Pract. 2024 Jan 11. pii: S0344-0338(24)00029-3. [Epub ahead of print]254 155118

The effect of p53 on the activity of NRF2 and NDRG2 genes through apoptotic pathway in IDH-wildtype glioblastoma.

Maher Kurdi, Saleh Baeesa, Motaz M Fadul, Alaa Alkhotani, Shadi Alkhayyat, Mohammed M Karami, Taghreed Alsinani, Yousef Katib, Amany A Fathaddin, Eyad Faizo, Ahmed I Lary, Majid Almansouri, Yazid Maghrabi, Mohammed A Alyousef, Bassam Addass.

   BACKGROUND: Tumor suppressor (p53) acts to integrate multiple stress signals into diverse antiproliferative responses. Its potential to transactivate or downregulate genes through apoptotic pathway in IDH-wildtype glioblastoma has never been explored.
METHODS: A group of twenty patients diagnosed with IDH-wildtype glioblastoma, were tested for p53 expression and NDRG2/NRF2 genes activity through protein and gene profiling assays. The connotation between these elements has been explored.
RESULTS: The mean patients' age was 64-years. All tumors were IDH-wildtype. p53 was expressed in 12 tumors and absent in 8 tumors. The activity of NDRG2 gene was downregulated in all cases. The activity of NRF2 gene was upregulated in 17 tumors and downregulated in 3 tumors. There was a significant statistical difference in PFS among tumors exhibiting different levels of p53 expression and NDRG2 gene activity [p-value= 0.025], in which 12 tumors with downregulated NDRG2 expression and positive p53 expression had earlier tumor recurrence. This statistical difference in PFS was insignificant when we compared p53 expression with NRF2 gene activity [p-value= 0.079].
CONCLUSIONS: During cell cycle arrest at G2 phase, p53 expression in IDH-wildtype glioblastoma in elderly individuals, coupled with the downregulation of NDRG2 gene activity, led to an aberrant increase in tumor cell proliferation and accelerated tumor recurrence. However, the influence of p53 on NRF2 gene activity was found to be insignificant.

Keywords:  IDH-wildtype Glioblastoma; NDRG2; NRF2; P53; Tumor Recurrence

DOI:  https://doi.org/10.1016/j.prp.2024.155118
Redox Biol. 2023 Dec 27. pii: S2213-2317(23)00412-3. [Epub ahead of print]70 103011

Thiol starvation triggers melanoma state switching in an ATF4 and NRF2-dependent manner.

Madlen Meinert, Christina Jessen, Anita Hufnagel, Julia Katharina Charlotte Kreß, Mychal Burnworth, Theo Däubler, Till Gallasch, Thamara Nishida Xavier da Silva, Ancély Ferreira Dos Santos, Carsten Patrick Ade, Werner Schmitz, Susanne Kneitz, José Pedro Friedmann Angeli, Svenja Meierjohann.

The cystine/glutamate antiporter xCT is an important source of cysteine for cancer cells. Once taken up, cystine is reduced to cysteine and serves as a building block for the synthesis of glutathione, which efficiently protects cells from oxidative damage and prevents ferroptosis. As melanomas are particularly exposed to several sources of oxidative stress, we investigated the biological role of cysteine and glutathione supply by xCT in melanoma. xCT activity was abolished by genetic depletion in the Tyr::CreER; BrafCA; Ptenlox/+ melanoma model and by acute cystine withdrawal in melanoma cell lines. Both interventions profoundly impacted melanoma glutathione levels, but they were surprisingly well tolerated by murine melanomas in vivo and by most human melanoma cell lines in vitro. RNA sequencing of human melanoma cells revealed a strong adaptive upregulation of NRF2 and ATF4 pathways, which orchestrated the compensatory upregulation of genes involved in antioxidant defence and de novo cysteine biosynthesis. In addition, the joint activation of ATF4 and NRF2 triggered a phenotypic switch characterized by a reduction of differentiation genes and induction of pro-invasive features, which was also observed after erastin treatment or the inhibition of glutathione synthesis. NRF2 alone was capable of inducing the phenotypic switch in a transient manner. Together, our data show that cystine or glutathione levels regulate the phenotypic plasticity of melanoma cells by elevating ATF4 and NRF2.

DOI: https://doi.org/10.1016/j.redox.2023.103011
Genes Genomics. 2024 Jan 19.

PSMD12 promotes non-small cell lung cancer progression through activating the Nrf2/TrxR1 pathway.

Junqi Lv, Shengmao Ma, Xiaowen Wang, Jifang Dang, Fuchun Ma.

   BACKGROUND: Non-small cell lung cancer (NSCLC) contributes to the vast majority of cancer-related deaths. Proteasome 26S subunit, non-ATPase 12 (PSMD12), a subunit of 26S proteasome complex, is known to play the tumor-promoting role in several types of cancer but its function in NSCLC remains elusive.
OBJECTIVE: To explore the role and underlying mechanisms of PSMD12 in NSCLC.
METHODS: The PSMD12 expression in human normal lung epithelial cell line (BEAS-2B) and four NSCLC cell lines (A549, NCI-H1299, NCI-H1975, Calu-1) were determined by qRT-PCR and western blot. Malignant phenotypes of NSCLC cells were detected by CCK-8, EdU staining, immunofluorescence staining for E-cadherin, flow cytometry, and Transwell assays to assess cell viability, proliferation, epithelial-mesenchymal transition (EMT), apoptosis, migration and invasion. Dual luciferase assay was used to verify the regulatory role of transcription factor on the promoter.
RESULTS: We identified the upregulation of PSMD12 in NSCLC tissues based on the GEO datasets, which further verified in NSCLC and BEAS-2B cell lines. PSMD12 knockdown significantly suppressed malignant behaviors of NSCLC cells, including cell growth, invasion, and migration, while PSMD12 overexpression presented the opposite effects. Interestingly, we found that PSMD12 upregulated the tumor-promoting factor TrxR1 mRNA expression. For its potential mechanisms, we demonstrated that PSMD12 elevated transcription factor Nrf2 protein level and promoted Nrf2 nuclear translocation. And Nrf2 further increased TrxR1 promoter activity and enhanced TrxR1 transcription. Meanwhile, we proved that TrxR1 overexpression erased the inhibitory effect of PSMD12 knockdown.
CONCLUSION: PSMD12 promotes NSCLC progression by activating the Nrf2/TrxR1 pathway, providing a novel prognostic and therapeutic target for NSCLC treatment.

Keywords:  Non-small cell lung cancer; Nrf2; PSMD12; TrxR1

DOI:  https://doi.org/10.1007/s13258-023-01484-5
Anticancer Drugs. 2024 Jan 22.

APOC1 reduced anti-PD-1 immunotherapy of nonsmall cell lung cancer via the transformation of M2 into M1 macrophages by ferroptosis by NRF2/HO-1.

Langhua Mei, Jian Long, Shue Wu, Meie Mei, Di Mei, Huaping Qiu.

The treatment strategy for nonsmall cell lung cancer (NSCLC) has always been a hot topic of concern, and its treatment strategies are also emerging. This experiment wants to know the effects of apolipoprotein C1 (APOC1) in immunotherapy of NSCLC. APOC1 mRNA and protein expression were upregulated in lung cancer tissue of patients with NSCLC. programmed cell death protein 1 (PD-1) mRNA expression was negatively correlated with PD-1 mRNA expression in patients. The survival rate of APOC1 high expression was lower than that of low expression in patients with NSCLC. APOC1 gene reduced the transformation of M2 into M1 macrophages (TMMM). APOC1 gene promoted cell growth, and the gene reduced ferroptosis of NSCLC. APOC1-induced nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (NRF2/HO-1) signaling pathway. Sh-APOC1 gene reduced cell growth in mice of NSCLC through the inhibition of NRF2/HO-1 signaling pathway. The inhibition of NRF2 reduced the TMMM by APOC1. The activation of NRF2 reduced the TMMM by si-APOC1. In conclusion, APOC1 reduced anti-PD-1 immunotherapy of NSCLC via the TMMM by ferroptosis by NRF2/HO-1, suggesting that targeting this mechanism of APOC1 may be a feasible strategy for anti-PD-1 immunotherapy for NSCLC.

DOI: https://doi.org/10.1097/CAD.0000000000001573
Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdad160

Exploring the multifaceted role of NRF2 in brain physiology and cancer: A comprehensive review.

Maya M Moubarak, Antonio C Pagano Zottola, Claire M Larrieu, Sylvain Cuvellier, Thomas Daubon, Océane C B Martin.

  Chronic oxidative stress plays a critical role in the development of brain malignancies due to the high rate of brain oxygen utilization and concomitant production of reactive oxygen species. The nuclear factor-erythroid-2-related factor 2 (NRF2), a master regulator of antioxidant signaling, is a key factor in regulating brain physiology and the development of age-related neurodegenerative diseases. Also, NRF2 is known to exert a protective antioxidant effect against the onset of oxidative stress-induced diseases, including cancer, along with its pro-oncogenic activities through regulating various signaling pathways and downstream target genes. In glioblastoma (GB), grade 4 glioma, tumor resistance, and recurrence are caused by the glioblastoma stem cell population constituting a small bulk of the tumor core. The persistence and self-renewal capacity of these cell populations is enhanced by NRF2 expression in GB tissues. This review outlines NRF2's dual involvement in cancer and highlights its regulatory role in human brain physiology and diseases, in addition to the development of primary brain tumors and therapeutic potential, with a focus on GB.

Keywords:  Brain physiology; NRF2; glioblastoma stem cells; oxidative stress; therapeutic resistance

DOI:  https://doi.org/10.1093/noajnl/vdad160
Chem Biol Interact. 2024 Jan 17. pii: S0009-2797(24)00021-8. [Epub ahead of print] 110875

Piperlongumine inhibits esophageal squamous cell carcinoma in vitro and in vivo by triggering NRF2/ROS/TXNIP/NLRP3-dependent pyroptosis.

Yue Cui, Xiao-Bo Chen, Ying Liu, Qian Wang, Jie Tang, Man-Jun Chen.

  Pyroptosis, a type of programmed cell death, is characterized by cell swelling with bubbles, and the release of inflammatory cell cytokines. Piperlongumine (PL) is a natural bioactive product extracted from Piper longum L, which can effectively exert anti-tumor activities in cancer. However, the effects and the exact molecular mechanisms of PL in esophageal squamous carcinoma (ESCC) remain unclear. This research aimed to investigate the role and mechanism of PL on ESCC in vitro and in vivo. In vitro, the MTT results showed that the IC50 of PL in ESCC cells was 28.55 μM. Moreover, PL significantly suppressed malignant behavior by promoting pyroptosis of ESCC cells by inhibiting proliferation, migration, invasion, and colony formation of KYSE-30 cells, up-regulating expressions of ASC, Cleaved-caspase-1, NLRP3, and GSDMD, while inducing the generation of ROS. Further, NRF2 knockdown promoted TXNIP expression, while overexpression of NRF2 inhibited TXNIP expression. However, after PL treatment, this effect was reversed. In addition, PL significantly inhibited the malignant behavior of ESCC cells while the inhibitory effects were reversed by DMF (NRF2 activator) or NAC (ROS eliminator) treatment. Finally, PL markedly increased expressions of ASC, Cleaved-caspase-1, NLRP3, GSDMD, and the generation of ROS while the effects were reversed by TXNIP knockdown or RUS (TXNIP inhibitor) treatment. In vivo, the KYSE-30 xenograft model confirmed that PL inhibited the growth of ESCC transplanted tumors by promoting cell pyroptosis. In conclusion, the results suggested that PL inhibited the malignant behavior of ESCC cells in vitro and tumorigenesis of ESCC in vivo by inhibiting NRF2 and promoting ROS-TXNIP-NLRP3-mediated pyroptosis.

Keywords:  Esophageal squamous cell carcinoma; NRF2; Piperlongumine; Pyroptosis; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.cbi.2024.110875
ACS Pharmacol Transl Sci. 2024 Jan 12. 7(1): 195-211

Novel Sulforaphane Analog Disrupts Phosphatidylinositol-3-Kinase-Protein Kinase B Pathway and Inhibits Cancer Cell Progression via Reactive Oxygen Species-Mediated Caspase-Independent Apoptosis.

Ananya Dutta, Satyajit Halder, Ishani Bhaumik, Utsab Debnath, Debashis Dhara, Anup Kumar Misra, Kuladip Jana.

Sulforaphane, a naturally occurring isothiocyanate, has gained attention due to its tremendous anticancer potential. Thus, an array of sulforaphane analogs were synthesized and evaluated for their cytotoxic potentials on a wide range of malignant cell lines. Among these derivatives, compound 4a displayed exceptional potency in inhibiting the proliferation of cancer cell lines and a negligible effect on normal cell lines through G2/M phase arrest. The lead compound induced reactive oxygen species (ROS)-mediated mitochondrial dysfunction, leading to apoptosis. Further mechanistic studies established the interaction of the compound 4a with the insulin-like growth factor-1 receptor (IGF-R1) and blocking of the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (PKB/Akt) pathway. This led to suppression of nuclear factor erythroid 2-related factor 2 (NRF-2) protein expression, thus increasing the free radicals in the tumor cells. Moreover, compound 4a induced ROS-mediated caspase-independent apoptosis. Finally, compound 4a reduced tumor progression in a 4T1 injected BALB/c syngeneic mice tumor model. In conclusion, this study summarizes the mechanism of compound 4a-mediated ROS-mediated caspase-independent apoptosis. According to the study's findings, compound 4a can be used as a powerful new anticancer agent to enhance cancer treatment.

DOI: https://doi.org/10.1021/acsptsci.3c00229
Oral Oncol. 2024 Jan 12. pii: S1368-8375(23)00376-7. [Epub ahead of print]149 106680

Uncovering immune checkpoint heterogeneity in oral squamous cell carcinoma using single cell RNA-sequencing data highlights three subgroups of patients with distinct immune phenotypes.

Yannick Le Meitour, Jean-Philippe Foy, Mathilde Guinand, Lucas Michon, Andy Karabajakian, Jérôme Fayette, Pierre Saintigny, Karène Mahtouk.

   OBJECTIVES: In head and neck squamous cell carcinoma (HNSCC), PD-1/PD-L1 inhibitors remain inefficient in most patients, which points to the need for better characterization of immune checkpoint (ICP) molecule expression.
MATERIAL AND METHODS: We evaluated the expression of 22 ICP ligands (ICPL) in 2,176 malignant cells from 10 patients in a public single-cell RNA-sequencing dataset and in two cohorts of HNSCC patients for which gene expression data are available.
RESULTS: Based on ICPL expression, malignant cells formed three distinct clusters characterized either by a strong expression of ICPL together with an immune phenotype linked to IFN-γ response (cluster 1) or by a weak ICPL expression and little response to IFN-γ (clusters 2 and 3). Malignant cells from cluster 3 showed a high PD-L1 expression associated with NRF2 signature. The relevance of 3 groups of patients, i.e "high ICPL/high IFN-γ", "low ICPL/low IFN-γ" or "low ICPL/low IFN-γ/high PD-L1" was confirmed in a cohort of 259 OSCC whole tumor samples from TCGA and in the CLB-IHN cohort including patients treated with PD1/PD-L1 inhibitors. The heterogeneous expression of ICPL among patients' malignant cells was associated with immunologically distinct microenvironments, evaluated with the "hot/cold" and the Tumor microenvironment (TME) classification. Finally, the "low ICPL/low IFN-γ/high PD-L1" group 3 displayed a poor prognosis in the TCGA cohort.
CONCLUSION: Hence, the global picture of ICPL gene expression in malignant cells from HNSCC patients may contribute to the broader issue of improving immunotherapy strategies though a better stratification of patients and the design of new treatment combinations.

Keywords:  Head and neck squamous cell carcinoma; Immune checkpoint; Immunotherapy; PD-L1; scRNAseq

DOI:  https://doi.org/10.1016/j.oraloncology.2023.106680
J Photochem Photobiol B. 2024 Jan 13. pii: S1011-1344(24)00006-X. [Epub ahead of print]251 112846

Glucocorticoid receptor mediated sensitization of colon cancer to photodynamic therapy induced cell death.

Ushasri Chilakamarthi, Namita S Mahadik, Tithi Bhattacharyya, Palivela Siva Gangadhar, Lingamallu Giribabu, Rajkumar Banerjee.

  Photodynamic therapy (PDT) is a clinically approved, non-invasive alternate cancer therapy. A synthetic glucocorticoid (GC), dexamethasone (Dex) has previously been demonstrated to sensitize cancer cells to chemotherapy. However, to the best of our knowledge, the sensitization effect of GCs on PDT has not yet been investigated. We hypothesized that glucocorticoid receptor (GR) targeting can selectively make cancer cells more sensitive to PDT treatment, as PDT induces hypoxia wherein GR-activity gets enhanced. In addition, Dex was reported to act against the PDT-induced cell survival pathways like HIF-1α, NRF2, NF-κB, STAT3 etc. Thus, both the treatments can complement each other and may result in increasing the effectiveness of combination therapy. Hence, in this study, we developed liposomal formulations of our previously reported PDT agent P-Nap, either alone (D1P-Nap) or in combination with Dex (D1XP-Nap) to elucidate the sensitization effect. Interestingly, our RT-PCR results in hypoxic conditions showed down-regulation of HIF-1α and over expression of GR-activated genes for glucose-6-phosphatase (G6Pase) and PEPCK enzymes, indicating prominent GR-transactivation. We also observed higher phototoxicity in CT26.WT cells treated with D1XP-Nap PDT under hypoxic conditions as compared to normoxic conditions. These effects were reversed when cells were pre-treated with RU486, a competitive inhibitor of GCs. Moreover, our in vivo findings of subcutaneous tumor model of Balb/C mice for colon cancer revealed a significant decrease in tumor volume as well as considerable enhancement in the survivability of PDT treated tumor-bearing mice when Dex was present in the formulation. A high Bax/Bcl-xL ratio, high p53 expression, enhanced E-cadherin expression and down-regulation of pro-tumorigenic transcription factors NF-κB and c-Myc were found in tumor lysates from mice treated with D1XP-Nap under PDT, indicating GR-mediated sensitization of the tumor to PDT-induced cell death and enhancement of life-span for tumor bearing mice.

Keywords:  Cancer; Combination therapy; Dexamethasone; Photodynamic therapy; Sensitization

DOI:  https://doi.org/10.1016/j.jphotobiol.2024.112846
Biomed Res Int. 2024 ;2024 9840106

Retracted: MCU That Is Transcriptionally Regulated by Nrf2 Augments Malignant Biological Behaviors in Oral Squamous Cell Carcinoma Cells.

BioMed Research International.

[This retracts the article DOI: 10.1155/2021/6650791.].

DOI: https://doi.org/10.1155/2024/9840106
Biomed Res Int. 2024 ;2024 9860506

Retracted: The Impact of Catalpol on Proliferation, Apoptosis, Migration, and Oxidative Stress of Lung Cancer Cells Based on Nrf2/ARE Signaling.

BioMed Research International.

[This retracts the article DOI: 10.1155/2022/5621341.].

DOI: https://doi.org/10.1155/2024/9860506