bims-nurfca 2023-06-11 papers

Issue of 2023–06–11
five papers selected by
Caner Geyik, Istinye University

Biochem Genet. 2023 Jun 08.

Nrf2/HO-1 Alleviates Disulfiram/Copper-Induced Ferroptosis in Oral Squamous Cell Carcinoma.

Accumulating evidence indicates that the disulfiram/copper complex (DSF/Cu) has been shown to have potent antitumor activity against various cancers. This research evaluated the effects and probable mechanisms of DSF/Cu on oral squamous cell carcinoma (OSCC). In this study, we report the toxicity of the DSF/Cu to OSCC both in vitro and in vivo. Our study showed that DSF/Cu reduced the proliferation and clonogenicity of OSCC cells. DSF/Cu also induced ferroptosis. Importantly, we confirmed that DSF/Cu could increase the free iron pool, enhance lipid peroxidation, and eventually result in ferroptosis cell death. Inhibition of NRF2 or HO-1 enhances the sensitivity of OSCC cells to DSF/Cu-induced ferroptosis. DSF/Cu inhibited the xenograft growth of OSCC cells by suppressing the expression of Nrf2/HO-1. In conclusion, these results provide experimental evidence that Nrf2/HO-1 alleviates DSF/Cu-induced ferroptosis in OSCC. We propose that this therapy could be a novel strategy for treating OSCC.

Keywords: DSF/Cu; Ferroptosis; Nrf2/HO-1; OSCC

DOI: https://doi.org/10.1007/s10528-023-10405-w

Biochem Soc Trans. 2023 Jun 09. pii: BST20220352. [Epub ahead of print]

Small molecule and peptide inhibitors of βTrCP and the βTrCP-NRF2 protein-protein interaction.

Uzma Jaffry, Geoff Wells.

The E3 ligase beta-transducin repeat-containing protein (βTrCP) is an essential component of the ubiquitin-proteasome system that is responsible for the maintenance of cellular protein levels in human cells. Key target substrates for degradation include inhibitor of nuclear factor kappa B, programmed cell death protein 4 and forkhead box protein O3, alongside the transcription factor nuclear factor erythroid-2-related factor 2 (NRF2) that is responsible for cellular protection against oxidative damage. The tumour suppressive nature of many of its substrates and the overexpression of βTrCP observed in various cancers support a potential therapeutic role for inhibitors in the treatment of cancer. A small molecule substituted pyrazolone, GS143, and the natural product erioflorin have been identified as inhibitors of βTrCP and protect its targets from proteasomal degradation. Modified peptides based on the sequences of native substrates have also been reported with KD values in the nanomolar range. This review describes the current status of inhibitors of this E3 ligase. The scope for further inhibitor design and the development of PROTAC and molecular glue-type structures is explored in the context of βTrCP as an example of WD40 domain-containing proteins that are gaining attention as drug targets.

Keywords: NRF2; cancer; drug discovery and design; βTrCP

DOI: https://doi.org/10.1042/BST20220352

Front Oncol. 2023 ;13 1108729

Junction of the redox dynamic, orchestra of signaling, and altered metabolism in regulation of T- cell lymphoma.

Shantanu Singh, Akhilendra Kumar Maurya.

T-cell lymphoma is a hematologic neoplasm derived from the lymphoid lineage. It belongs to a diverse group of malignant disorders, mostly affecting the young population worldwide, that vary with respect to molecular features as well as genetic and clinical complexities. Cancer cells rewire the cellular metabolism, persuading it to meet new demands of growth and proliferation. Furthermore, the metabolic alterations and heterogeneity are aberrantly driven in cancer by a combination of genetic and non-genetic factors, including the tumor microenvironment. New insight into cancer metabolism highlights the importance of nutrient supply to tumor development and therapeutic responses. Importantly, oxidative stress due to an imbalance in the redox status of reactive species via exogenous and/or endogenous factors is closely related to multiple aspects of cancer. This alters the signaling pathways governed through the multiple intracellular signal transduction and transcription factors, leading to tumor progression. These oncogenic signaling molecules are regulated through different redox sensors, including nuclear factor-erythroid 2 related factor 2 (Nrf2), phase-II antioxidant enzyme, and NQO1 (NADPH quinone oxidoreductase (1). The existing understanding of the molecular mechanisms of T-cell lymphoma regulation through the cross-talk of redox sensors under the influence of metabolic vulnerability is not well explored. This review highlights the role of the redox dynamics, orchestra of signaling, and genetic regulation involved in T-cell lymphoma progression in addition to the challenges to their etiology, treatment, and clinical response in light of recent updates.

Keywords: NF-κB; Nrf2; T-cell lymphoma; cancer metabolism; redox status; signaling pathways

DOI: https://doi.org/10.3389/fonc.2023.1108729

Biochem Pharmacol. 2023 Jun 06. pii: S0006-2952(23)00230-7. [Epub ahead of print] 115639

Exploring Cell Competition for the Prevention and Therapy of Esophageal Squamous Cell Carcinoma.

Kristen Knapp, Vincent Verchio, Olivia Coburn-Flynn, Yahui Li, Zhaohui Xiong, Jamin C Morrison, David D Shersher, Francis Spitz, Xiaoxin Chen.

Esophageal squamous cell carcinoma (ESCC) is characterized by the development of cancer in the esophageal squamous epithelium through a step-by-step accumulation of genetic, epigenetic and histopathological alterations. Recent studies have demonstrated that cancer-associated gene mutations exist in histologically normal or precancerous clones of the human esophageal epithelium. However, only a small proportion of such mutant clones will develop ESCC, and most ESCC patients develop only one cancer. This suggests that most of these mutant clones are kept in a histologically normal state by neighboring cells with higher competitive fitness. When some of the mutant cells evade cell competition, they become "super-competitors" and develop into clinical cancer. It is known that human ESCC is composed of a heterogeneous population of cancer cells that interact with and influence their environment and neighbors. During cancer therapy, these cancer cells not only respond to therapeutic agents but also compete with each other. Therefore, competition between ESCC cells within the same ESCC tumor is a constantly dynamic process. However, it remains challenging to fine-tune the competitive fitness of various clones for therapeutic benefits. In this review, we will explore the role of cell competition in carcinogenesis, cancer prevention, and therapy, using NRF2, NOTCH pathway, and TP53 as examples. We believe that cell competition is a research area with promising targets for clinical translation. Manipulating cell competition may help improve the prevention and therapy of ESCC.

Keywords: Cell competition; Esophageal squamous cell carcinoma; NOTCH; NRF2; P53

DOI: https://doi.org/10.1016/j.bcp.2023.115639

Cancer Res. 2023 Jun 08. pii: CAN-22-2605. [Epub ahead of print]

Characterizing evolutionary dynamics reveals strategies to exhaust the spectrum of subclonal resistance in EGFR-mutant lung cancer.

Nina Müller, Carina Lorenz, Jenny Ostendorp, Felix S Heisel, Ulrich P Friese, Maria Cartolano, Dennis Plenker, Hannah L Tumbrink, Alena Heimsoeth, Philipp Baedeker, Sandra Ortiz-Cuaran, Jonathan Weiss, Reinhard Büttner, Martin Peifer, Roman K Thomas, Martin L Sos, Johannes Berg, Johannes Brägelmann.

The emergence of resistance to targeted therapies restrains their efficacy. The development of rational-ly guided drug combinations could overcome this currently insurmountable clinical challenge. However, our limited understanding of the trajectories that drive the outgrowth of resistant clones in cancer cell populations precludes design of drug combinations to forestall resistance. Here, we propose an iterative treatment strategy coupled with genomic profiling and genome-wide CRISPR activation screening to systematically extract and define pre-existing resistant subpopulations in an EGFR-driven lung cancer cell line. Integrating these modalities identifies several resistance mechanisms, including activation of YAP/TAZ signaling by WWTR1 amplification, and estimated the associated cellular fitness for mathematical population modeling. These observations led to the development of a combina-tion therapy that eradicated resistant clones in large cancer cell line populations by exhausting the spectrum of genomic resistance mechanisms. However, a small fraction of cancer cells was able to enter a reversible non-proliferative state of drug tolerance. This sub-population exhibited mesenchy-mal properties, NRF2 target gene expression and sensitivity to ferroptotic cell death. Exploiting this induced collateral sensitivity by GPX4 inhibition clears drug tolerant populations and led to tumor cell eradication. Overall, this experimental in vitro data and theoretical modeling demonstrate why targeted mono- and dual therapies will likely fail in sufficiently large cancer cell populations to limit long-term efficacy. Our approach is not tied to a particular driver mechanism and can be used to systematically assess and ideally exhaust the resistance landscape for different cancer types to rationally design com-bination therapies.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-2605