bims-glucam 2023-12-03 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023‒12‒03
fifteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Telomerase reverse transcriptase induces targetable alterations in glutathione and nucleotide biosynthesis in glioblastomas.
A PD-L1-targeting Regulator for Metabolic Reprogramming to Enhance Glutamine Inhibition-mediated Synergistic Antitumor Metabolic And Immune Therapy.
Osteoclast-Cancer Cell Metabolic Crosstalk Confers PARP Inhibitor Resistance in Bone Metastatic Breast Cancer.
The essential role of glutamine metabolism in diabetic cardiomyopathy: A review.
The immunometabolic ecosystem in cancer.
Glutathione promotes the synergistic effects of venetoclax and azacytidine against myelodysplastic syndrome‑refractory anemia by regulating the cell cycle.
Reductive carboxylation of glutamine as a potential target in acute myeloid leukemia.
The metabolic repression effect of carbon-ion radiotherapy in synchronous hormone-sensitive oligometastatic prostate cancer.
Lysine-372-dependent SUMOylation inhibits the enzymatic activity of glutamine synthases.
SIRT5-mediated ME2 desuccinylation promotes cancer growth by enhancing mitochondrial respiration.
Inhibition of the urea cycle by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin increases serum ammonia levels in mice.
Membrane transporters in cell physiology, cancer metabolism and drug response.
The cross-talk between macrophages and tumor cells as a target for cancer treatment.
Oxidative stress regulation and related metabolic pathways in epithelial-mesenchymal transition of breast cancer stem cells.
Glutathione-responsive PROTAC for targeted degradation of ERα in breast cancer cells.

bioRxiv. 2023 Nov 16. pii: 2023.11.14.566937. [Epub ahead of print]

Telomerase reverse transcriptase induces targetable alterations in glutathione and nucleotide biosynthesis in glioblastomas.

Suresh Udutha, Céline Taglang, Georgios Batsios, Anne Marie Gillespie, Meryssa Tran, Sabrina M Ronen, Johanna Ten Hoeve, Thomas G Graeber, Pavithra Viswanath.

Telomerase reverse transcriptase (TERT) is essential for glioblastoma (GBM) proliferation. Delineating metabolic vulnerabilities induced by TERT can lead to novel GBM therapies. We previously showed that TERT upregulates glutathione (GSH) pool size in GBMs. Here, we show that TERT acts via the FOXO1 transcription factor to upregulate expression of the catalytic subunit of glutamate-cysteine ligase (GCLC), the rate-limiting enzyme of de novo GSH synthesis. Inhibiting GCLC using siRNA or buthionine sulfoximine (BSO) reduces synthesis of 13 C-GSH from [U- 13 C]-glutamine and inhibits clonogenicity. However, GCLC inhibition does not induce cell death, an effect that is associated with elevated [U- 13 C]-glutamine metabolism to glutamate and pyrimidine nucleotide biosynthesis. Mechanistically, GCLC inhibition activates MYC and leads to compensatory upregulation of two key glutamine-utilizing enzymes i.e., glutaminase (GLS), which generates glutamate from glutamine, and CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotatase), the enzyme that converts glutamine to the pyrimidine nucleotide precursor dihydroorotate. We then examined the therapeutic potential of inhibiting GLS and CAD in combination with GCLC. 6-diazo-5-oxy-L-norleucin (DON) is a potent inhibitor of glutamine-utilizing enzymes including GLS and CAD. The combination of BSO and DON suppresses GSH and pyrimidine nucleotide biosynthesis and is synergistically lethal in GBM cells. Importantly, in vivo stable isotope tracing indicates that combined treatment with JHU-083 (a brain-penetrant prodrug of DON) and BSO abrogates synthesis of GSH and pyrimidine nucleotides from [U- 13 C]-glutamine and induces tumor shrinkage in mice bearing intracranial GBM xenografts. Collectively, our studies exploit a mechanistic understanding of TERT biology to identify synthetically lethal metabolic vulnerabilities in GBMs.SIGNIFICANCE: Using in vivo stable isotope tracing, metabolomics, and loss-of-function studies, we demonstrate that TERT expression is associated with metabolic alterations that can be synergistically targeted for therapy in glioblastomas.

DOI: https://doi.org/10.1101/2023.11.14.566937
Adv Mater. 2023 Nov 28. e2309094

A PD-L1-targeting Regulator for Metabolic Reprogramming to Enhance Glutamine Inhibition-mediated Synergistic Antitumor Metabolic And Immune Therapy.

Xiao-Kang Jin, Shi-Man Zhang, Jun-Long Liang, Shun-Kang Zhang, You-Teng Qin, Qian-Xiao Huang, Chuan-Jun Liu, Xian-Zheng Zhang.

  Inhibition of glutamine metabolism in tumor cells can cause metabolic compensation-mediated glycolysis enhancement and PD-L1 upregulation-induced immune evasion, significantly limiting the therapeutic efficacy of glutamine inhibitors. Here, inspired by the specific binding of receptor and ligand, a PD-L1-targeting metabolism and immune regulator (PMIR) was constructed by decorating the glutaminase inhibitor (BPTES)-loading zeolitic imidazolate framework (ZIF) with PD-L1-targeting peptides for regulating the metabolism within the tumor microenvironment (TME) to improve immunotherapy. At tumor sites, PMIR inhibited glutamine metabolism of tumor cells for elevating glutamine levels within the TME to improve the function of immune cells. Ingeniously, the accompanying PD-L1 upregulation on tumor cells caused self-amplifying accumulation of PMIR through PD-L1 targeting, while also blocking PD-L1, which had the effects of converting enemies into friends. Meanwhile, PMIR exactly offset the compensatory glycolysis, while disrupting the redox homeostasis in tumor cells via the cooperation of components of the ZIF and BPTES. These together caused immunogenic cell death of tumor cells and relieved PD-L1-mediated immune evasion, further reshaping the immunosuppressive TME and evoking robust immune responses to effectively suppress bilateral tumor progression and metastasis. This work proposed a rational strategy to surmount the obstacles in glutamine inhibition for boosting existing clinical treatments. This article is protected by copyright. All rights reserved.

Keywords:  Drug delivering; Glutamine inhibition; Metabolic reprogramming; Self-amplifying PD-L1 targeting; Tumor immunotherapy

DOI:  https://doi.org/10.1002/adma.202309094
Cancer Res. 2023 Dec 01.

Osteoclast-Cancer Cell Metabolic Crosstalk Confers PARP Inhibitor Resistance in Bone Metastatic Breast Cancer.

Huijuan Fan, Zhanao Xu, Ke Yao, Bingxin Zheng, Yuan Zhang, Xuxiang Wang, Tengjiang Zhang, Xuan Li, Haitian Hu, Bin Yue, Zeping Hu, Hanqiu Zheng.

The majority of patients with late-stage breast cancer develop distal bone metastases. The bone microenvironment can affect response to therapy, and uncovering the underlying mechanisms could help identify improved strategies for treating bone metastatic breast cancer. Here, we observed that osteoclasts reduced the sensitivity of breast cancer cells to DNA damaging agents, including cisplatin and the PARP inhibitor (PARPi) olaparib. Metabolic profiling identified elevated glutamine production by osteoclasts. Glutamine supplementation enhanced the survival of breast cancer cells treated with DNA damaging agents, while blocking glutamine uptake increased sensitivity and suppressed bone metastasis. GPX4, the critical enzyme responsible for glutathione oxidation, was upregulated in cancer cells following PARPi treatment through stress-induced ATF4-dependent transcriptional programming. Increased glutamine uptake and GPX4 upregulation concertedly enhanced glutathione metabolism in cancer cells to help neutralize oxidative stress and generate PARPi resistance. Analysis of paired patient samples of primary breast tumors and bone metastases revealed significant induction of GPX4 in bone metastases. Combination therapy utilizing PARPi and zoledronate, which blocks osteoclast activity and thereby reduces the microenvironmental glutamine supply, generated a synergistic effect in reducing bone metastasis. These results identify a role for glutamine production by bone-resident cells in supporting metastatic cancer cells to overcome oxidative stress and develop resistance to DNA-damaging therapies.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-1443
Medicine (Baltimore). 2023 Nov 24. 102(47): e36299

The essential role of glutamine metabolism in diabetic cardiomyopathy: A review.

Yiying Zhang.

Diabetic cardiomyopathy (DCM) is a pathophysiological condition caused by diabetes mellitus and is the leading cause of diabetes mellitus-related mortality. The pathophysiology of DCM involves various processes, such as oxidative stress, inflammation, ferroptosis, and abnormal protein modification. New evidence indicates that dysfunction of glutamine (Gln) metabolism contributes to the pathogenesis of DCM by regulating these pathophysiological mechanisms. Gln is a conditionally essential amino acid in the human body, playing a vital role in maintaining cell function. Although the precise molecular mechanisms of Gln in DCM have yet to be fully elucidated, recent studies have shown that supplementing with Gln improves cardiac function in diabetic hearts. However, excessive Gln may worsen myocardial injury in DCM by generating a large amount of glutamates or increasing O-GlcNacylation. To highlight the potential therapeutic method targeting Gln metabolism and its downstream pathophysiological mechanisms, this article aims to review the regulatory function of Gln in the pathophysiological mechanisms of DCM.

DOI: https://doi.org/10.1097/MD.0000000000036299
Nat Immunol. 2023 Dec;24(12): 2008-2020

The immunometabolic ecosystem in cancer.

Glenn R Bantug, Christoph Hess.

Our increased understanding of how key metabolic pathways are activated and regulated in malignant cells has identified metabolic vulnerabilities of cancers. Translating this insight to the clinics, however, has proved challenging. Roadblocks limiting efficacy of drugs targeting cancer metabolism may lie in the nature of the metabolic ecosystem of tumors. The exchange of metabolites and growth factors between cancer cells and nonmalignant tumor-resident cells is essential for tumor growth and evolution, as well as the development of an immunosuppressive microenvironment. In this Review, we will examine the metabolic interplay between tumor-resident cells and how targeted inhibition of specific metabolic enzymes in malignant cells could elicit pro-tumorigenic effects in non-transformed tumor-resident cells and inhibit the function of tumor-specific T cells. To improve the efficacy of metabolism-targeted anticancer strategies, a holistic approach that considers the effect of metabolic inhibitors on major tumor-resident cell populations is needed.

DOI: https://doi.org/10.1038/s41590-023-01675-y
Exp Ther Med. 2023 Dec;26(6): 574

Glutathione promotes the synergistic effects of venetoclax and azacytidine against myelodysplastic syndrome‑refractory anemia by regulating the cell cycle.

Xiaobo Wang, Lihua Yuan, Bo Lu, Dongjun Lin, Xiaojun Xu.

  Azacitidine is a DNA methyltransferase inhibitor that has been used as a singular agent for the treatment of myelodysplastic syndrome-refractory anemia with excess blast-1 and -2 (MDS-RAEB I/II). However, recurrence and overall response rates following this treatment remain unsatisfactory. The combination of azacitidine and venetoclax has been used for the clinical treatment of a variety of hematological diseases due to the synergistic killing effect of the two drugs. Venetoclax is a BCL-2 inhibitor that can inhibit mitochondrial metabolism. In addition, azacitidine has been shown to reduce the levels of myeloid cell leukemia 1 (MCL-1) in acute myeloid leukemia cells. MCL-1 is an anti-apoptotic protein and a potential source of resistance to venetoclax. However, the mechanism underlying the effects of combined venetoclax and azacitidine treatment remains to be fully elucidated. In the present study, the molecular mechanism underlying the impact of venetoclax on the efficacy of azacitidine was investigated by examining its effects on cell cycle progression. SKM-1 cell lines were treated in vitro with 0-2 µM venetoclax and 0-4 µM azacytidine. After 24, 48 and 72 h of treatment, the impact of the drugs on the cell cycle was assessed by flow cytometry. Following drug treatment, changes in cellular glutamine metabolism pathways was analyzed using western blotting (ATF4, CHOP, ASCT2, IDH2 and RB), quantitative PCR (ASCT2 and IDH2), liquid chromatography-mass spectrometry (α-KG, succinate and glutathione) and ELISA (glutamine and glutaminase). Venetoclax was found to inhibit mitochondrial activity though the alanine-serine-cysteine transporter 2 (ASCT2) pathway, which decreased glutamine uptake. Furthermore, venetoclax partially antagonized the action of azacitidine through this ASCT2 pathway, which was reversed by glutathione (GSH) treatment. These results suggest that GSH treatment can potentiate the synergistic therapeutic effects of venetoclax and azacitidine combined treatment on a myelodysplastic syndrome-refractory anemia cell line at lower concentrations.

Keywords:  azacitidine; glutathione; mitochondrial glutamine metabolism; myelodysplastic syndrome-refractory anemia; venetoclax

DOI:  https://doi.org/10.3892/etm.2023.12274
Oncotarget. 2023 Dec 01. 14 947-948

Reductive carboxylation of glutamine as a potential target in acute myeloid leukemia.

Alessia Roma, Lawrence D Goodridge, Paul A Spagnuolo.



Keywords:  acute myeloid leukemia; complex II; metabolism; mitochondria; reductive carboxylation

DOI:  https://doi.org/10.18632/oncotarget.28474
Front Endocrinol (Lausanne). 2023 ;14 1291653

The metabolic repression effect of carbon-ion radiotherapy in synchronous hormone-sensitive oligometastatic prostate cancer.

Zhenshan Zhang, Yulei Pei, Wei Hu, Yushan Xue, Renli Ning, Xiaomao Guo, Yun Sun, Qing Zhang.

  Background: Metastatic prostate cancer (PCa) poses a significant public health concern. While radiation therapy (RT) is commonly utilized in the treatment of synchronous oligometastatic hormone sensitive prostate cancer (OM-HSPC), the occurrence of biochemical recurrence still remains. To deepen our understanding and optimize the outcome of OM-HSPC, we conducted this study to investigate the characteristics of PCa progression and explore potential synergistic mechanisms involving carbon-ion radiotherapy (CIRT) and neoadjuvant androgen deprivation treatment (naADT) in OM-HSPC.Methods: Metabolomic analysis was conducted with 72 urinary samples (at different timepoints) from 33 Patients (T2-3N0M0-1b) and 18 healthy volunteers by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). MetaboAnalyst website and R software were employed for metabolomic analysis and visualization (using the criteria of p value < 0.05 and |FC|>1.5). The impact of CIRT on metabolism were further verified and explored through in vitro and in vivo experiments.
Results: We found that most metabolites (223 out of 233) were upregulated in treatment-naïve PCa samples compared to healthy samples. After naADT, 60 core risk metabolites were still significantly related to PCa's progression, and the glutamine level which was significantly higher in OM-HSPC compared to other groups. Remarkably, after CIRT treatment, the glutamine levels in OM-HSPC were significantly reduced to the level of healthy samples. Experiments further confirmed CIRT's ability to suppress glutamine levels in PCa tumors and its potential enhancement with glutamine deprivation intervention.
Conclusion: CIRT with naADT might synergistically inhibit HS-OMPC development, progression and even the ADT resistance through glutamine metabolism repression, moreover, the glutamine metabolism might be a novel target to further improved the efficacy of CIRT.

Keywords:  carbon ion radiotherapy; glutamine; hormone treatment; metabolomics; metastatic prostate cancer

DOI:  https://doi.org/10.3389/fendo.2023.1291653
FASEB J. 2023 Dec;37(12): e23319

Lysine-372-dependent SUMOylation inhibits the enzymatic activity of glutamine synthases.

Ting Ling, Siyi Li, Huan Chen, Qiuping Wang, Jing Shi, Yirong Li, Wenjun Bao, Kunming Liang, Hai-Long Piao.

Glutamine synthetase (GS) is a crucial enzyme involved in de novo synthesis of glutamine and participates in several biological processes, including nitrogen metabolism, nucleotide synthesis, and amino acid synthesis. Post-translational modification makes GS more adaptable to the needs of cells, and acetylation modification of GS at double sites has attracted considerable attention. Despite very intensive research, how SUMOylation affects GS activity at a molecular level remains unclear. Here, we report that previously undiscovered GS SUMOylation which is deficient mutant K372R of GS exhibits more bluntness under glutamine starvation. Mechanistically, glutamine deprivation triggers the GS SUMOylation, and this SUMOylation impaired the protein stability of GS, within a concomitant decrease in enzymatic activity. In addition, we identified SAE1, Ubc9, and PIAS1 as the assembly enzymes of GS SUMOylation respectively. Furthermore, Senp1/2 functions as a SUMO-specific protease to reverse the SUMOylation of GS. This study provides the first evidence that SUMOylation serves as a regulatory mechanism for determining the GS enzymatic activity, contributing to understanding the GS regulation roles in various cellular and pathophysiological processes.

DOI: https://doi.org/10.1096/fj.202301462RR
Cell Death Differ. 2023 Nov 25.

SIRT5-mediated ME2 desuccinylation promotes cancer growth by enhancing mitochondrial respiration.

Peng Teng, Kaisa Cui, Surui Yao, Bojian Fei, Feng Ling, Chaoqun Li, Zhaohui Huang.

Mitochondrial malic enzyme 2 (ME2), which catalyzes the conversion of malate to pyruvate, is frequently upregulated during tumorigenesis and is a potential target for cancer therapy. However, the regulatory mechanism underlying ME2 activity is largely unknown. In this study, we demonstrate that ME2 is highly expressed in human colorectal cancer (CRC) tissues, and that ME2 knockdown inhibits the proliferation of CRC cells. Furthermore, we reveal that ME2 is succinylated and identify Sirtuins 5 (SIRT5) as an ME2 desuccinylase. Glutamine deprivation directly enhances the interaction of SIRT5 with ME2 and thus promotes SIRT5-mediated desuccinylation of ME2 at lysine 346, activating ME2 enzymatic activity. Activated ME2 significantly enhances mitochondrial respiration, thereby counteracting the effects of glutamine deprivation and supporting cell proliferation and tumorigenesis. Additionally, the levels of succinylated ME2 at K346 and SIRT5 in CRC tissues, which are negatively correlated, are associated with patient prognosis. These observations suggest that SIRT5-catalyzed ME2 desuccinylation is a key signaling event through which cancer cells maintain mitochondrial respiration and promote CRC progression under glutamine deficiency conditions, offering the possibility of targeting SIRT5-mediated ME2 desuccinylation for CRC treatment.

DOI: https://doi.org/10.1038/s41418-023-01240-y
J Biol Chem. 2023 Nov 25. pii: S0021-9258(23)02528-0. [Epub ahead of print] 105500

Inhibition of the urea cycle by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin increases serum ammonia levels in mice.

Giovan N Cholico, Russell R Fling, Warren J Sink, Rance Nault, Tim Zacharewski.

  The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor known for mediating the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. TCDD induces non-alcoholic fatty liver disease (NAFLD)-like pathologies including simple steatosis that can progress to steatohepatitis with fibrosis and bile duct proliferation in male mice. Dose-dependent progression of steatosis to steatohepatitis with fibrosis by TCDD has been associated with metabolic reprogramming, including the disruption of amino acid metabolism. Here, we used targeted metabolomic analysis to reveal dose-dependent changes in the level of ten serum and eleven hepatic amino acids in mice upon treatment with TCDD. Bulk RNAseq and protein analysis showed TCDD repressed CPS1, OTS, ASS1, ASL, and GLUL, all of which are associated with the urea cycle and glutamine biosynthesis. Urea and glutamine are end products of the detoxification and excretion of ammonia, a toxic byproduct of amino acid catabolism. Furthermore, we found that the catalytic activity of OTC, a rate-limiting step in the urea cycle was also dose-dependently repressed. These results are consistent with an increase in circulating ammonia. Collectively, the repression of the urea and glutamate-glutamine cycles increased circulating ammonia levels and the toxicity of TCDD.

Keywords:  2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); ammonia; aryl hydrocarbon receptor (AHR); liver; toxicogenomics

DOI:  https://doi.org/10.1016/j.jbc.2023.105500
Dis Model Mech. 2023 Nov 01. pii: dmm050404. [Epub ahead of print]16(11):

Membrane transporters in cell physiology, cancer metabolism and drug response.

Sara Alam, Emily Doherty, Paula Ortega-Prieto, Julia Arizanova, Louise Fets.

  By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types are, therefore, able to tailor their transporter expression signatures depending on their metabolic requirements, and the physiological importance of these proteins is illustrated by their mis-regulation in a number of disease states. In cancer, transporter expression is heterogeneous, and the SLC family has been shown to facilitate the accumulation of biomass, influence redox homeostasis, and also mediate metabolic crosstalk with other cell types within the tumour microenvironment. This Review explores the roles of membrane transporters in physiological and malignant settings, and how these roles can affect drug response, through either indirect modulation of sensitivity or the direct transport of small-molecule therapeutic compounds into cells.

Keywords:  Cancer Metabolism; Drug Uptake; Pharmacology; Transporters

DOI:  https://doi.org/10.1242/dmm.050404
Front Oncol. 2023 ;13 1259034

The cross-talk between macrophages and tumor cells as a target for cancer treatment.

Muhammad Aizaz, Aakif Khan, Faisal Khan, Maria Khan, Ebraheem Abdu Musad Saleh, Maryum Nisar, Natalia Baran.

  Macrophages represent an important component of the innate immune system. Under physiological conditions, macrophages, which are essential phagocytes, maintain a proinflammatory response and repair damaged tissue. However, these processes are often impaired upon tumorigenesis, in which tumor-associated macrophages (TAMs) protect and support the growth, proliferation, and invasion of tumor cells and promote suppression of antitumor immunity. TAM abundance is closely associated with poor outcome of cancer, with impediment of chemotherapy effectiveness and ultimately a dismal therapy response and inferior overall survival. Thus, cross-talk between cancer cells and TAMs is an important target for immune checkpoint therapies and metabolic interventions, spurring interest in it as a therapeutic vulnerability for both hematological cancers and solid tumors. Furthermore, targeting of this cross-talk has emerged as a promising strategy for cancer treatment with the antibody against CD47 protein, a critical macrophage checkpoint recognized as the "don't eat me" signal, as well as other metabolism-focused strategies. Therapies targeting CD47 constitute an important milestone in the advancement of anticancer research and have had promising effects on not only phagocytosis activation but also innate and adaptive immune system activation, effectively counteracting tumor cells' evasion of therapy as shown in the context of myeloid cancers. Targeting of CD47 signaling is only one of several possibilities to reverse the immunosuppressive and tumor-protective tumor environment with the aim of enhancing the antitumor response. Several preclinical studies identified signaling pathways that regulate the recruitment, polarization, or metabolism of TAMs. In this review, we summarize the current understanding of the role of macrophages in cancer progression and the mechanisms by which they communicate with tumor cells. Additionally, we dissect various therapeutic strategies developed to target macrophage-tumor cell cross-talk, including modulation of macrophage polarization, blockade of signaling pathways, and disruption of physical interactions between leukemia cells and macrophages. Finally, we highlight the challenges associated with tumor hypoxia and acidosis as barriers to effective cancer therapy and discuss opportunities for future research in this field.

Keywords:  TAMs; cancer progression; cross-talk; hematological malignancies; macrophages; tumor cells

DOI:  https://doi.org/10.3389/fonc.2023.1259034
Stem Cell Res Ther. 2023 Nov 28. 14(1): 342

Oxidative stress regulation and related metabolic pathways in epithelial-mesenchymal transition of breast cancer stem cells.

Raheleh Farahzadi, Behnaz Valipour, Ezzatollah Fathi, Samaneh Pirmoradi, Ommoleila Molavi, Soheila Montazersaheb, Zohreh Sanaat.

  Epithelial-mesenchymal transition (EMT) is a cell remodeling process in which epithelial cells undergo a reversible phenotype switch via the loss of adhesion capacity and acquisition of mesenchymal characteristics. In other words, EMT activation can increase invasiveness and metastatic properties, and prevent the sensitivity of tumor cells to chemotherapeutics, as mesenchymal cells have a higher resistance to chemotherapy and immunotherapy. EMT is orchestrated by a complex and multifactorial network, often linked to episodic, transient, or partial events. A variety of factors have been implicated in EMT development. Based on this concept, multiple metabolic pathways and master transcription factors, such as Snail, Twist, and ZEB, can drive the EMT. Emerging evidence suggests that oxidative stress plays a significant role in EMT induction. One emerging theory is that reducing mitochondrial-derived reactive oxygen species production may contribute to EMT development. This review describes how metabolic pathways and transcription factors are linked to EMT induction and addresses the involvement of signaling pathways.

Keywords:  Epithelial–mesenchymal transition; Metabolic pathways; Oxidative stress; Reactive oxygen species; Signaling pathways; Transcription factors

DOI:  https://doi.org/10.1186/s13287-023-03571-6
Bioorg Med Chem. 2023 Nov 08. pii: S0968-0896(23)00374-7. [Epub ahead of print]96 117526

Glutathione-responsive PROTAC for targeted degradation of ERα in breast cancer cells.

Zhili Zhou, Heli Fan, Dehao Yu, Fengying Shi, Qianqian Li, Zhenjian Zhang, Xiaolu Wang, Xuejun Zhang, Cheng Dong, Huabing Sun, Wenyi Mi.

ERα (estrogen receptor-α)-targeting PROTACs (PROteolysis TArgeting Chimeras) have emerged as a novel and promising modality for breast cancer therapeutics. However, ERα PROTACs-induced degradation in normal tissues raises concerns about potential off-tissue toxicity. Tumor microenvironment-responsive strategy provides potential for specific control of the PROTAC's on-target degradation activity. The glutathione (GSH) level has been reported to be significantly increased in tumor cells. Here, we designed a GSH-responsive ERα PROTAC, which is generated by conjugating an o-nitrobenzenesulfonyl group to the hydroxyl group of VHL-based ERα PROTAC through a nucleophilic substitution reaction. The o-nitrobenzenesulfonyl group as a protecting group blocks the bioactivity of ERα PROTAC (ER-P1), and that can be specifically recognized and removed by highly abundant GSH in cancer cells. Consequently, the GSH-responsive ERα PROTAC (GSH-ER-P1) exhibits significantly enhanced degradation of ERα in cancer cells compared to that in normal cells, leading to a remarkable inhibition of breast cancer cell proliferation and less toxic effects on normal cells. This study provides a potentially valuable strategy for breast cancer treatment using tumor microenvironment-responsive PROTACs.

DOI: https://doi.org/10.1016/j.bmc.2023.117526