bims-nurfca 2023-01-29 papers

Issue of 2023–01–29
five papers selected by
Caner Geyik, Istinye University

Chem Res Toxicol. 2023 Jan 24.

Role of Human Aldo-Keto Reductases and Nuclear Factor Erythroid 2-Related Factor 2 in the Metabolic Activation of 1-Nitropyrene via Nitroreduction in Human Lung Cells.

Anthony L Su, Trevor M Penning.

1-Nitropyrene (1-NP) is a constituent of diesel exhaust and classified as a group 2A probable human carcinogen. The metabolic activation of 1-NP by nitroreduction generates electrophiles that can covalently bind DNA to form mutations to contribute to cancer causation. NADPH-dependent P450 oxidoreductase (POR), xanthine oxidase (XO), aldehyde oxidase (AOX), and NAD(P)H/quinone oxidoreductase 1 (NQO1) may catalyze 1-NP nitroreduction. We recently found that human recombinant aldo-keto reductases (AKRs) 1C1-1C3 catalyze 1-NP nitroreduction. NQO1 and AKR1C1-1C3 are genes induced by nuclear factor erythroid 2-related factor 2 (NRF2). Despite this knowledge, the relative importance of these enzymes and NRF2 to 1-NP nitroreduction is unknown. We used a combination of pharmacological and genetic approaches to assess the relative importance of these enzymes and NRF2 in the aerobic nitroreduction of 1-NP in human bronchial epithelial cells, A549 and HBEC3-KT. 1-NP nitroreduction was assessed by the measurement of 1-aminopyrene (1-AP), the six-electron reduced metabolite of 1-NP, based on its intrinsic fluorescence properties (λex and λem). We found that co-treatment of 1-NP with salicylic acid, an AKR1C1 inhibitor, or ursodeoxycholate, an AKR1C2 inhibitor, for 48 h decreased 1-AP production relative to 1-NP treatment alone (control) in both cell lines. R-Sulforaphane or 1-(2-cyano-3,12,28-trioxooleana-1,9(11)-dien-28-yl)-1H-imidazole (CDDO-Im), two NRF2 activators, each increased 1-AP production relative to control only in HBEC3-KT cells, which have inducible NRF2. Inhibitors of POR, NQO1, and XO failed to modify 1-AP production relative to control in both cell lines. Importantly, A549 wild-type cells with constitutively active NRF2 produced more 1-AP than A549 cells with heterozygous expression of NFE2L2/NRF2, which were able to produce more 1-AP than A549 cells with homozygous knockout of NFE2L2/NRF2. Together, these data show dependence of 1-NP metabolic activation on AKR1Cs and NRF2 in human lung cells. This is the second example whereby NFE2L2/NRF2 is implicated in the carcinogenicity of diesel exhaust constituents.

DOI: https://doi.org/10.1021/acs.chemrestox.2c00337

Clin Cancer Res. 2023 Jan 23. pii: CCR-22-2747. [Epub ahead of print]

Dysregulation and epigenetic reprogramming of NRF2 signaling axis promote acquisition of cisplatin resistance and metastasis in Head and Neck Squamous Cell Carcinoma.

Abdullah A Osman, Emre Arslan, Mason Bartels, Chieko Michikawa, Antje Lindemann, Katarzyna Tomczak, Wangjie Yu, Vlad Sandulache, Wencai Ma, Li Shen, Jing Wang, Anand K Singh, Mitchell J Frederick, Nakia D Spencer, Jeffrey Kovacs, Timothy Heffernan, William F Symmans, Kunal Rai, Jeffrey N Myers.

PURPOSE: CDDP based chemotherapy is a first-line treatment for patients with advanced head and neck squamous cell carcinomas (HNSCCs), despite a high rate of treatment failures, acquired resistance and subsequent aggressive behavior. The purpose of this study was to delineate the mechanism of CDDP resistance and metastasis in HNSCC. We investigated the role of NRF2 pathway activation as a driven event for tumor progression and metastasis of HNSCC.
EXPERIMENTAL DESIGN: Human HNSCC cell lines that are highly resistant to CDDP were generated. Clonogenic survival assays and a mouse model of oral cancer were used to examine the impact of NRF-2 activation in vitro and in vivo on CDDP sensitivity and development of metastasis. Western blotting, immunostaining, whole exome sequencing, single cell transcriptomic and epigenomic profiling platforms were performed to dissect clonal evolution and molecular mechanisms Results: Implantation of CDDP resistant HNSCC cells into the tongues of nude mice resulted in a very high rate of distant metastases. The CDDP resistant cells had significantly higher expression of NRF2 pathway genes in the presence of newly acquired KEAP1 mutations, or via epigenomic activation of target genes. Knockdown of NRF2 or restoration of the wtKEAP1 genes re-sensitized resistant cells to CDDP and decreased distant metastasis. Finally, treatment with inhibitor of GLS1, a NRF2 target gene, alleviated CDDP resistance.
CONCLUSIONS: CDDP resistance and development of distant metastasis are associated with dysregulated and epigenetically reprogrammed KEAP1-NRF2 signaling pathway. A strategy targeting KEAP1/NRF2 pathway or glutamine metabolism deserves further clinical investigation in patients with CDDP resistant head and neck tumors.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-2747

Cell Biol Int. 2023 Jan 22.

Cinchonine-induced cell death in pancreatic cancer cells by downregulating RRP15.

Feng Liang, Ying Lv, Xiao Qiao, Shu Zhang, Shanshan Shen, Changcheng Wang, Guifang Xu, Xiaoping Zou, Lei Wang, Bin Zhang.

Pancreatic cancer is characterized by poor prognosis and high mortality, while its treatment remains unsatisfactory. Cinchonine, a natural compound present in cinchona bark, is a potential anticancer drug. Whether cinchonine is of relevance to pancreatic cancer therapeutics is unclear. This research showed that the ribosomal RNA-processing 15 homolog (RRP15) expression is decreased in the pancreatic cancer, and RRP15 knockdown inhibited autophagy, and caused apoptosis in pancreatic cancer cells. Cinchonine treatment inhibits the expression of RRP15 and autophagy, and caused apoptosis by leading to the activation of Nrf2 axis in pancreatic cancer cells. Taken together, the above results indicate that cinchonine treatment inhibited autophagy and induced apoptosis through activating Nrf2 axis by downregulating RRP15 in pancreatic cancer cells.

Keywords: Nrf2; RRP15; apoptosis; autophagy; cinchonine; pancreatic cancer

DOI: https://doi.org/10.1002/cbin.11987

Sci Rep. 2023 Jan 25. 13(1): 1384

Cyperotundone combined with adriamycin induces apoptosis in MCF-7 and MCF-7/ADR cancer cells by ROS generation and NRF2/ARE signaling pathway.

Wenna Shao, Xinzhao Wang, Zhaoyun Liu, Xiang Song, Fukai Wang, Xiaoyu Liu, Zhiyong Yu.

Breast cancer has become the most prevalent cancer, globally. Adriamycin is a first-line chemotherapeutic agent, however, cancer cells acquire resistance to it, which is one of the most common causes of treatment failure. ROS and NRF2 are essential oxidative stress factors that play a key role in the oxidative stress process and are associated with cancer. Our goal is to create novel therapeutic drugs or chemical sensitizers that will improve chemotherapy sensitivity. The optimal concentration and duration for MCF-7 and MCF-7/ADR cells in ADR and CYT were determined using the CCK-8 assay. We found that ADR + CYT inhibited the activity of MCF-7 and MCF-7/ADR cells in breast cancer, as well as causing apoptosis in MCF-7 and MCF-7/ADR cells and blocking the cell cycle in the G0/G1 phase. ADR + CYT induces apoptosis in MCF-7 and MCF-7/ADR cells through ROS generation and the P62/NRF2/HO-1 signaling pathway. In breast cancer-bearing nude mice, ADR + CYT effectively suppressed tumor development in vivo. Overall, our findings showed that CYT in combination with ADR has potent anti-breast cancer cell activity both in vivo and in vitro, suggesting CYT as the main drug used to improve chemosensitivity.

DOI: https://doi.org/10.1038/s41598-022-26767-x

Small. 2023 Jan 24. e2206981

CRISPR/Cas9 and Chlorophyll Coordination Micelles for Cancer Treatment by Genome Editing and Photodynamic Therapy.

Chen Zhang, Xiaojie Wang, Gengqi Liu, He Ren, Jingang Liu, Zhen Jiang, Yumiao Zhang.

CRISPR/Cas9-based gene therapy and photodynamic therapy both show promise for cancer treatment but still have their drawbacks limited by tumor microenvironment and long treatment duration. Herein, CRISPR/Cas9 genome editing and photodynamic strategy for a synergistic anti-tumor therapeutic modality is merged. Chlorophyll (Chl) extracted from natural green vegetables is encapsulated in Pluronic F127 (F127) micelles and Histidine-tagged Cas9 can be effectively chelated onto micelles via metal coordination by simple incubation, affording Cas9-Chl@F127 micelles. Mg2+ acts as an enzyme cofactor to correlatively enhance Cas9 gene-editing activity. Upon laser irradiation, Chl as an effective photosensitizer generates reactive oxygen species (ROS) to kill tumor cells. Meanwhile, CRISPR/Cas9, mediated by dual deliberately designed gRNAs of APE1 and NRF2, can reprogram the tumor microenvironment by increasing the intracellular oxygen accumulation and impairing the oxidative defense system of tumor cells. Cas9-Chl@F127 micelles can responsively release Cas9 in the presence of abundant ATP or low pH in tumor cells. In a murine tumor model, Cas9-Chl@F127 complexed with dual gRNAs including APE1 and NRF2 significantly inhibits the tumor growth. Taken together, Cas9-Chl@F127 micelles, representing the first Chl-based green biomaterial for the delivery of Cas9, show great promise for the synergistic anti-tumor treatment by PDT and gene editing.

Keywords: CRISPR-Cas9; enzymatic cofactor; gene therapy; photodynamic therapy; responsive release

DOI: https://doi.org/10.1002/smll.202206981