bims-nurfca 2023-06-04 papers

Issue of 2023–06–04
four papers selected by
Caner Geyik, Istinye University

ACS Appl Mater Interfaces. 2023 May 30.

Transferrin-Targeted Cascade Nanoplatform for Inhibiting Transcription Factor Nuclear Factor Erythroid 2-Related Factor 2 and Enhancing Ferroptosis Anticancer Therapy.

Wenjie Chen, Li Xie, Can Lv, Erqun Song, Xiaokang Zhu, Yang Song.

Ferroptosis, an iron-dependent cell death driven by the lethal levels of lipid peroxidation (LPO), becomes a promising anticancer strategy. However, the anticancer efficacy of ferroptosis is often hindered by the activation of nuclear factor erythrocyte 2-associated factor 2 (Nrf2), which is an indispensable regulator of the cellular antioxidant balance by preventing the accumulation of intracellular reactive oxygen species (ROS). Herein, we present a rational design of a Tf-targeted cascade nanoplatform TPM@AM based on mesoporous polydopamine (MPDA) co-encapsulating a ferroptosis inducer (artesunate, ART) and an Nrf2-specific inhibitor (ML385) to enhance intracellular ROS and therefore amplify ferrotherapy. Transferrin (Tf) can specifically recognize the transferrin receptor (TfR) on the surface of the cell membrane, which binds and transports iron into cells. When TPM@AM is endocytosed, the high-acid tumor microenvironment and laser irradiation trigger the collapse of MPDA to release ART and ML385. Furthermore, MPDA endows the nanoplatform with photothermal capability. The nanoplatform exhibits high efficiency for synergistic tumor suppression, representing a spatiotemporal controllable therapeutic strategy for precise synergistic cancer therapy.

Keywords: Nrf2; anticancer therapy; artesunate; ferroptosis; transferrin

DOI: https://doi.org/10.1021/acsami.3c01499

Cell Cycle. 2023 May 28. 1-18

TRIM13 inhibits cell proliferation and induces autophagy in lung adenocarcinoma by regulating KEAP1/NRF2 pathway.

Bo Yu, Yu Zhou, Jinxi He.

Lung adenocarcinoma (LUAD) is the most common type of lung cancer. Tripartite motif 13 (TRIM13) is a member of TRIM protein family and is downregulated in multiple cancers, especially non-small cell lung cancers (NSCLC). In this study, we investigated anti-tumor mechanism of TRIM13 in non-small cell lung cancer tissues and cell lines. First, the mRNA and protein levels of TRIM13 in LUAD tissue and cells were measured. TRIM13 was overexpressed on LUAD cells to investigate the effects on cell proliferation, apoptosis, oxidative stress, p62 ubiquitination, and autophagy activation. Finally, mechanistic role of TRIM13 in regulating the Keap1/Nrf2 pathway was investigated. Results indicated that low level of TRIM13 mRNA and protein expression was found in LUAD tissue and cells. Overexpression of TRIM13 in LUAD cancer cells suppressed their proliferation, increased apoptosis, and oxidative stress, ubiquitinated p62, and activated autophagy via the RING finger domain of TRIM13. Furthermore, TRIM13 showed interaction with p62 and mediated its ubiquitination and degradation in LUAD cells. Mechanistically, TRIM13 exerted the tumor suppressor functions in LUAD cells by negatively regulating Nrf2 signaling and downstream antioxidants, which was further confirmed by in vivo data from xenografts. In conclusion, TRIM13 behaves like a tumor suppressor and triggers autophagy in LUAD cells by mediating p62 ubiquitination via KEAP1/Nrf2 pathway. Our findings provide a novel insight into targeted therapy plans for LUAD.

Keywords: Lung adenocarcinoma; TRIM13; autophagy; oxidative stress; ubiquitination

DOI: https://doi.org/10.1080/15384101.2023.2216504

Front Oncol. 2023 ;13 1125855

PGM3 inhibition shows cooperative effects with erastin inducing pancreatic cancer cell death via activation of the unfolded protein response.

Barbara Zerbato, Maximilian Gobbi, Tobias Ludwig, Virginia Brancato, Alex Pessina, Luca Brambilla, Andre Wegner, Ferdinando Chiaradonna.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor patient prognosis. Remarkably, PDAC is one of the most aggressive and deadly tumor types and is notorious for its resistance to all types of treatment. PDAC resistance is frequently associated with a wide metabolic rewiring and in particular of the glycolytic branch named Hexosamine Biosynthetic Pathway (HBP).
Methods: Transcriptional and bioinformatics analysis were performed to obtain information about the effect of the HBP inhibition in two cell models of PDAC. Cell count, western blot, HPLC and metabolomics analyses were used to determine the impact of the combined treatment between an HBP's Phosphoglucomutase 3 (PGM3) enzyme inhibitor, named FR054, and erastin (ERA), a recognized ferroptosis inducer, on PDAC cell growth and survival.
Results: Here we show that the combined treatment applied to different PDAC cell lines induces a significant decrease in cell proliferation and a concurrent enhancement of cell death. Furthermore, we show that this combined treatment induces Unfolded Protein Response (UPR), NFE2 Like BZIP Transcription Factor 2 (NRF2) activation, a change in cellular redox state, a greater sensitivity to oxidative stress, a major dependence on glutamine metabolism, and finally ferroptosis cell death.
Conclusion: Our study discloses that HBP inhibition enhances, via UPR activation, the ERA effect and therefore might be a novel anticancer mechanism to be exploited as PDAC therapy.

Keywords: cell death; erastin; ferroptosis; hexosamine biosynthetic pathway; pancreatic cancer cells; unfolded protein response

DOI: https://doi.org/10.3389/fonc.2023.1125855

Front Oncol. 2023 ;13 1178686

The genomic landscape of sensitivity to arsenic trioxide uncovered by genome-wide CRISPR-Cas9 screening.

Jun-Zhu Chen, Li-Na Wang, Xue-Qun Luo, Yan-Lai Tang.

Introduction: Arsenic trioxide (ATO) is a promising anticancer drug for hematological malignancy. Given the dramatic efficacy of acute promyelocytic leukemia (APL), ATO has been utilized in other types of cancers, including solid tumors. Unfortunately, the results were not comparable with the effects on APL, and the resistance mechanism has not been clarified yet. This study intends to identify relevant genes and pathways affecting ATO drug sensitivity through genome-wide CRISPR-Cas9 knockdown screening to provide a panoramic view for further study of ATO targets and improved clinical outcomes.
Methods: A genome-wide CRISPR-Cas9 knockdown screening system was constructed for ATO screening. The screening results were processed with MAGeCK, and the results were subjected to pathway enrichment analysis using WebGestalt and KOBAS. We also performed protein-protein interaction (PPI) network analysis using String and Cytoscape, followed by expression profiling and survival curve analysis of critical genes. Virtual screening was used to recognize drugs that may interact with the hub gene.
Results: We applied enrichment analysis and identified vital ATO-related pathways such as metabolism, chemokines and cytokines production and signaling, and immune system responses. In addition, we identified KEAP1 as the top gene relating to ATO resistance. We found that KEAP1 expression was higher in the pan-cancer, including ALL, than in normal tissue. Patients with acute myeloid leukemia (AML) with higher KEAP1 expression had worse overall survival (OS). A virtual screen showed that etoposide and eltrombopag could bind to KEAP1 and potentially interact with ATO.
Discussion: ATO is a multi-target anticancer drug, and the key pathways regulating its sensitivity include oxidative stress, metabolism, chemokines and cytokines, and the immune system. KEAP1 is the most critical gene regulating ATO drug sensitivity, which is related to AML prognosis and may bind to some clinical drugs leading to an interaction with ATO. These integrated results provided new insights into the pharmacological mechanism of ATO and potentiate for further applications in cancer treatments.

Keywords: CRISPR-Cas9 screening; KEAP1; arsenic trioxide; leukemia; virtual screening

DOI: https://doi.org/10.3389/fonc.2023.1178686