bims-meract 2024-12-15 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2024–12–15
25 papers selected by
Andrea Morandi, Università degli Studi di Firenze

Fasting-mimicking diet potentiates anti-tumor effects of CDK4/6 inhibitors against breast cancer by suppressing NRAS- and IGF1-mediated mTORC1 signaling.
Influence of lactate in resistance to anti‑PD‑1/PD‑L1 therapy: Mechanisms and clinical applications (Review).
NAD+ METABOLISM RESTRICTION BOOSTS HIGH-DOSE MELPHALAN EFFICACY IN PATIENTS WITH MULTIPLE MYELOMA.
Metabolic reprogramming, sensing, and cancer therapy.
Dual inhibition of oxidative phosphorylation and glycolysis exerts a synergistic antitumor effect on colorectal and gastric cancer by creating energy depletion and preventing metabolic switch.
Inhibition of Selenoprotein I promotes ferroptosis and reverses resistance to platinum chemotherapy by impairing Akt phosphorylation in ovarian cancer.
Targeting pivotal amino acids metabolism for treatment of leukemia.
Precise targeting of lipid metabolism in the era of immuno-oncology and the latest advances in nano-based drug delivery systems for cancer therapy.
Spermine synthase engages in macrophages M2 polarization to sabotage antitumor immunity in hepatocellular carcinoma.
A Novel Triptolide Nano-Liposome with Mitochondrial Targeting for Treatment of Hepatocellular Carcinoma.
Exploration of Novel Metabolic Features Reflecting Statin Sensitivity in Lung Cancer Cells.
Low PPP2R2A expression promotes sensitivity to CHK1 inhibition in high-grade serous ovarian cancer.
Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma.
Tissue factor promotes TREX1 protein stability to evade cGAS-STING innate immune response in pancreatic ductal adenocarcinoma.
How to deal with frenemy NRF2: Targeting NRF2 for chemoprevention and cancer therapy.
EFNA4-enhanced deubiquitination of SLC7A11 inhibits ferroptosis in hepatocellular carcinoma.
Mitochondrial signatures shape phenotype switching and apoptosis in response to PLK1 inhibitors.
miR-145-5p regulates hepatocellular carcinoma malignant advancement and immune escape via down-regulation of AcylCoA synthase ACSL4.
Autophagy inhibition induces AML cell death and enhances the efficacy of chemotherapy under hypoxia.
HMGB3 Contributes to Anti-PD-1 Resistance by Inhibiting IFN-γ-Driven Ferroptosis in TNBC.
Broadening horizons: the multifaceted role of ferroptosis in breast cancer.
Cancer-associated fibroblasts regulate mitochondrial metabolism and inhibit chemosensitivity via ANGPTL4-IQGAP1 axis in prostate cancer.
Polyanhydride Copolymer-Based Niclosamide Nanoparticles for Inhibiting Triple-Negative Breast Cancer: Metabolic Responses and Synergism with Paclitaxel.
The sedoheptulose kinase CARKL controls T-cell cytokine outputs and migration by promoting metabolic reprogramming.
Pleiotropic anti-cancer activities of novel non-covalent thioredoxin reductase inhibitors against triple negative breast cancer.

Drug Resist Updat. 2024 Dec 06. pii: S1368-7646(24)00140-7. [Epub ahead of print] 101182

Fasting-mimicking diet potentiates anti-tumor effects of CDK4/6 inhibitors against breast cancer by suppressing NRAS- and IGF1-mediated mTORC1 signaling.

Sebastian Brandhorst, Valter D Longo.

  Fasting-mimicking diet (FMD) cycles, defined as 3-5 day periods of a calorie-restricted, low-protein, low-carbohydrate, and high-fat diet, have emerged as a dietary approach to delay cancer initiation and progression in both autograft and xenograft mouse models and as a safe and feasible approach to decrease risk factors for cancer and other age-related pathologies in humans. A substantial number of pre-clinical studies focused on various tumor types have shown that fasting/FMDs can potentiate the efficacy of various standard-of-care cancer therapies but also modulate the immune system to promote a T cell-dependent attack of tumor cells. Importantly, combining drug treatment with fasting/FMDs can overcome acquired drug resistance which frequently emerges and reduces long-term treatment benefits. However, the mechanisms by which the FMD reverts resistance to CDK4/6i remain poorly understood. Here, Li and colleagues provide evidence that FMD cycles act as a wild card to reduce the activity of a signaling network that includes IGF-1, RAS, AKT, and mTOR-S6K to delay cancer progression and reverse the acquisition of drug resistance. These findings expand the mechanistic understanding of the FMD-mediated increase in drug efficacy and provide further evidence to support trials combining hormone therapy, CDK4/6 inhibitors, and FMD in breast cancer treatment. These new results on FMD cycles add an optimistic outlook to extend the efficacy of standard-of-care drugs that eventually become ineffective because of acquired resistance.

Keywords:  Cancer; Drug resistance; Fasting-mimicking diet

DOI:  https://doi.org/10.1016/j.drup.2024.101182
Mol Med Rep. 2025 Feb;pii: 48. [Epub ahead of print]31(2):

Influence of lactate in resistance to anti‑PD‑1/PD‑L1 therapy: Mechanisms and clinical applications (Review).

Yi Zeng, Yu Huang, Qiaoyun Tan, Ling Peng, Jian Wang, Fan Tong, Xiaorong Dong.

  Metabolic reprogramming is a prominent characteristic of tumor cells, evidenced by heightened secretion of lactate, which is linked to tumor progression. Furthermore, the accumulation of lactate in the tumor microenvironment (TME) influences immune cell activity, including the activity of macrophages, dendritic cells and T cells, fostering an immunosuppressive milieu. Anti‑programmed cell death protein 1 (PD‑1)/programmed death‑ligand 1 (PD‑L1) therapy is associated with a prolonged survival time of patients with non‑small cell lung cancer. However, some patients still develop resistance to anti‑PD‑1/PD‑L1 therapy. Lactate is associated with resistance to anti‑PD‑1/PD‑L1 therapy. The present review summarizes what is known about lactate metabolism in tumor cells and how it affects immune cell function. In addition, the present review emphasizes the relationship between lactate secretion and immunotherapy resistance. The present review also explores the potential for targeting lactate within the TME to enhance the efficacy of immunotherapy.

Keywords:  cancer immunity; immunotherapy; lactate; programmed cell death protein 1; programmed death‑ligand 1; tumor environment

DOI:  https://doi.org/10.3892/mmr.2024.13413
Blood Adv. 2024 Dec 11. pii: bloodadvances.2024013425. [Epub ahead of print]

NAD+ METABOLISM RESTRICTION BOOSTS HIGH-DOSE MELPHALAN EFFICACY IN PATIENTS WITH MULTIPLE MYELOMA.

Debora Soncini, Pamela Becherini, Francesco Ladisa, Silvia Ravera, Adithya Chedere, Elisa Gelli, Giulia Giorgetti, Claudia Martinuzzi, Francesco Piacente, Luca Mastracci, Claudia Veneziano, Gianluca Santamaria, Fiammetta Monacelli, Moustafa S Ghanem, Antonia Cagnetta, Fabio Guolo, Matteo Garibotto, Sara Aquino, Mario Passalacqua, Santina Bruzzone, Axel Bellotti, Michel A Duchosal, Aimable A Nahimana, Emanuele Angelucci, Chandra Nagasuma, Alessio Nencioni, Roberto Massimo Lemoli, Michele Cea.

Elevated levels of the nicotinamide adenine dinucleotide (NAD+)-generating enzyme nicotinamide phosphoribosyltransferase (NAMPT) are a common feature across numerous cancer types. Accordingly, we previously reported pervasive NAD+ dysregulation in Multiple Myeloma (MM) cells in association with upregulated NAMPT expression. Unfortunately, albeit being effective in preclinical models of cancer, NAMPT inhibition has proven ineffective in clinical trials due to the existence of alternative NAD+ production routes utilizing NAD+ precursors other than nicotinamide. Here, by leveraging mathematical modelling approaches integrated with transcriptome data, we defined the specific NAD+ landscape of MM cells and established that the Preiss-Handler pathway for NAD+-biosynthesis, which utilizes nicotinic acid as a precursor, supports NAD+ synthesis in MM cells via its key enzyme nicotinate phosphoribosyltransferase (NAPRT). Accordingly, we found that NAPRT confers resistance to NAD+ -depleting agents. Transcriptomic, metabolic, and bioenergetic profiling of NAPRT knock-out (KO) MM cells showed these to have weakened endogenous antioxidant defenses, increased propensity to oxidative stress, and enhanced genomic instability. Concomitant NAMPT inhibition further compounded the effects of NAPRT KO, effectively sensitizing MM cells to the chemotherapeutic drug, melphalan; NAPRT added-back fully rescues these phenotypes. Overall, our results propose comprehensive NAD+ biosynthesis inhibition, through simultaneously targeting NAMPT and NAPRT, as a promising strategy to be tested in randomized clinical trials involving transplant-eligible MM patients, especially those with more aggressive disease.

DOI: https://doi.org/10.1182/bloodadvances.2024013425
Cell Rep. 2024 Dec 12. pii: S2211-1247(24)01415-3. [Epub ahead of print]43(12): 115064

Metabolic reprogramming, sensing, and cancer therapy.

Youxiang Mao, Ziyan Xia, Wenjun Xia, Peng Jiang.

  The metabolic reprogramming of tumor cells is a crucial strategy for their survival and proliferation, involving tissue- and condition-dependent remodeling of certain metabolic pathways. While it has become increasingly clear that tumor cells integrate extracellular and intracellular signals to adapt and proliferate, nutrient and metabolite sensing also exert direct or indirect influences, although the underlying mechanisms remain incompletely understood. Furthermore, metabolic changes not only support the rapid growth and dissemination of tumor cells but also promote immune evasion by metabolically "educating" immune cells in the tumor microenvironment (TME). Recent studies have highlighted the profound impact of metabolic reprogramming on the TME and the potential of targeting metabolic pathways as a therapeutic strategy, with several enzyme inhibitors showing promising results in clinical trials. Thus, understanding how tumor cells alter their metabolic pathways and metabolically remodel the TME to support their survival and proliferation may offer new strategies for metabolic therapy and immunotherapy.

Keywords:  CP: Metabolism; immunometabolism; metabolic reprogramming; metabolite sensing; tumor metabolism; tumor therapy

DOI:  https://doi.org/10.1016/j.celrep.2024.115064
PLoS One. 2024 ;19(12): e0309700

Dual inhibition of oxidative phosphorylation and glycolysis exerts a synergistic antitumor effect on colorectal and gastric cancer by creating energy depletion and preventing metabolic switch.

Yuki Aisu, Nobu Oshima, Fuminori Hyodo, Abdelazim Elsayed Elhelaly, Akihiko Masuo, Tomoaki Okada, Shigeo Hisamori, Shigeru Tsunoda, Koya Hida, Tomonori Morimoto, Hiroyuki Miyoshi, Makoto M Taketo, Masayuki Matsuo, Leonard M Neckers, Yoshiharu Sakai, Kazutaka Obama.

Pyruvate is situated at the intersection of oxidative phosphorylation (OXPHOS) and glycolysis, which are the primary energy-producing pathways in cells. Cancer therapies targeting these pathways have been previously documented, indicating that inhibiting one pathway may lead to functional compensation by the other, resulting in an insufficient antitumor effect. Thus, effective cancer treatment necessitates concurrent and comprehensive suppression of both. However, whether a metabolic switch between the metabolic pathways occurs in colorectal and gastric cancer cells and whether blocking it by inhibiting both pathways has an antitumor effect remain to be determined. In the present study, we used two small molecules, namely OXPHOS and glycolysis inhibitors, to target pyruvate metabolic pathways as a cancer treatment in these cancer cells. OXPHOS and glycolysis inhibition each augmented the other metabolic pathway in vitro and in vivo. OXPHOS inhibition alone enhanced glycolysis and showed antitumor effects on colorectal and gastric cancer cells in vitro and in vivo. Moreover, glycolysis inhibition in addition to OXPHOS inhibition blocked the metabolic switch from OXPHOS to glycolysis, causing an energy depletion and deterioration of the tumor microenvironment that synergistically enhanced the antitumor effect of OXPHOS inhibitors. In addition, using hyperpolarized 13C-magnetic resonance spectroscopic imaging (HP-MRSI), which enables real-time and in vivo monitoring of molecules containing 13C, we visualized how the inhibitors shifted the flux of pyruvate and how this dual inhibition in colorectal and gastric cancer mouse models altered the two pathways. Integrating dual inhibition of OXPHOS and glycolysis with HP-MRSI, this therapeutic model shows promise as a future "cancer theranostics" treatment option.

DOI: https://doi.org/10.1371/journal.pone.0309700
MedComm (2020). 2024 Dec;5(12): e70033

Inhibition of Selenoprotein I promotes ferroptosis and reverses resistance to platinum chemotherapy by impairing Akt phosphorylation in ovarian cancer.

Jing Li, Mimi Chen, Dingwen Huang, Ziyin Li, Yu Chen, Jinhua Huang, Yuanqun Chen, Zhili Zhou, Zhiying Yu.

  Ovarian cancer (OV) ranks among the deadliest gynecological cancer, known for its high risk of relapse and metastasis, and a general resistance to conventional platinum-based chemotherapy. Selenoprotein I (SELENOI) is a crucial mediator implicated in human hereditary spastic paraplegia. However, its role in human tumors remains poorly elucidated. Here, we comprehensively analyzed SELENOI expression patterns, functions, and clinical implications across various malignancies through the integration of bulk transcriptomics, cancer databases, and in vitro and in vivo experiments. Pan-cancer analysis indicated upregulated SELENOI expression across various cancers, correlating with augmented malignancy, suppressed tumor immunity and poor prognosis. Knockdown of SELENOI caused G0/G1-phase cell cycle arrest and diminished aggressive cancer phenotypes in OV cells. Moreover, SELENOI inhibition augments ferroptosis and reverses the cisplatin resistance in OV cells by modulating Akt phosphorylation. Conversely, overexpression of SELENOI in OV cells enhanced therapeutic sensitivity to cisplatin by upregulating Akt phosphorylation. Importantly, in vivo studies demonstrated that SELENOI inhibition suppressed ovarian tumor growth and enhanced cisplatin's anticancer effects. These findings highlight the significant role of SELENOI in OV by modulating ferroptosis and chemotherapy resistance. Targeting SELENOI represents a promising therapeutic approach to promote the efficacy of platinum-based chemotherapy in OV, particularly in cases of resistance.

Keywords:  Akt phosphorylation; SELENOI; chemoresistance; ferroptosis; ovarian cancer

DOI:  https://doi.org/10.1002/mco2.70033
Heliyon. 2024 Dec 15. 10(23): e40492

Targeting pivotal amino acids metabolism for treatment of leukemia.

Jiankun Hong, Wuling Liu, Xiao Xiao, Babu Gajendran, Yaacov Ben-David.

  Metabolic reprogramming is a crucial characteristic of cancer, allowing cancer cells to acquire metabolic properties that support their survival, immune evasion, and uncontrolled proliferation. Consequently, targeting cancer metabolism has become an essential therapeutic strategy. Abnormal amino acid metabolism is not only a key aspect of metabolic reprogramming but also plays a significant role in chemotherapy resistance and immune evasion, particularly in leukemia. Changes in amino acid metabolism in tumor cells are typically driven by a combination of signaling pathways and transcription factors. Current approaches to targeting amino acid metabolism in leukemia include inhibiting amino acid transporters, blocking amino acid biosynthesis, and depleting specific amino acids to induce apoptosis in leukemic cells. Different types of leukemic cells rely on the exogenous supply of specific amino acids, such as asparagine, glutamine, arginine, and tryptophan. Therefore, disrupting the supply of these amino acids may represent a vulnerability in leukemia. This review focuses on the pivotal role of amino acids in leukemia metabolism, their impact on leukemic stem cells, and their therapeutic potential.

Keywords:  Amino-acid metabolism; Amino-acid transporters; Chemo-resistance; Immune invasion; Leukemia; Leukemic stem cells; Metabolic reprogramming; Signaling pathways

DOI:  https://doi.org/10.1016/j.heliyon.2024.e40492
Acta Pharm Sin B. 2024 Nov;14(11): 4717-4737

Precise targeting of lipid metabolism in the era of immuno-oncology and the latest advances in nano-based drug delivery systems for cancer therapy.

Hongyan Zhang, Yujie Li, Jingyi Huang, Limei Shen, Yang Xiong.

  Over the past decade, research has increasingly identified unique dysregulations in lipid metabolism within the tumor microenvironment (TME). Lipids, diverse biomolecules, not only constitute biological membranes but also function as signaling molecules and energy sources. Enhanced synthesis or uptake of lipids in the TME significantly promotes tumorigenesis and proliferation. Moreover, lipids secreted into the TME influence tumor-resident immune cells (TRICs), thereby aiding tumor survival against chemotherapy and immunotherapy. This review aims to highlight recent advancements in understanding lipid metabolism in both tumor cells and TRICs, with a particular emphasis on exogenous lipid uptake and endogenous lipid de novo synthesis. Targeting lipid metabolism for intervention in anticancer therapies offers a promising therapeutic avenue for cancer treatment. Nano-drug delivery systems (NDDSs) have emerged as a means to maximize anti-tumor effects by rewiring tumor metabolism. This review provides a comprehensive overview of recent literature on the development of NDDSs targeting tumor lipid metabolism, particularly in the context of tumor immunotherapy. It covers four key aspects: reprogramming lipid uptake, reprogramming lipolysis, reshaping fatty acid oxidation (FAO), and reshuffling lipid composition on the cell membrane. The review concludes with a discussion of future prospects and challenges in this burgeoning field of research.

Keywords:  Antitumor therapy; Cancer progression; Clinical treatment; Immune response; Lipid metabolic reprogramming; Lipid signaling; Nano-based drug delivery systems; Precision targeting

DOI:  https://doi.org/10.1016/j.apsb.2024.07.021
Cell Death Differ. 2024 Dec 10.

Spermine synthase engages in macrophages M2 polarization to sabotage antitumor immunity in hepatocellular carcinoma.

Yining Sun, Peitao Zhou, Junying Qian, Qin Zeng, Guangyan Wei, Yongsheng Li, Yuechen Liu, Yingjie Lai, Yizhi Zhan, Dehua Wu, Yuan Fang.

Disturbances in tumor cell metabolism reshape the tumor microenvironment (TME) and impair antitumor immunity, but the implicit mechanisms remain elusive. Here, we found that spermine synthase (SMS) was significantly upregulated in tumor cells, which correlated positively with the immunosuppressive microenvironment and predicted poor survival in hepatocellular carcinoma (HCC) patients. Via "subcutaneous" and "orthotopic" HCC syngeneic mouse models and a series of in vitro coculture experiments, we identified elevated SMS levels in HCC cells played a role in immune escape mainly through its metabolic product spermine, which induced M2 polarization of tumor-associated macrophages (TAMs) and subsequently corresponded with a decreased antitumor functionality of CD8+ T cells. Mechanistically, we discovered that spermine reprogrammed TAMs mainly by activating the PI3K-Akt-mTOR-S6K signaling pathway. Spermine inhibition in combination with immune checkpoint blockade effectively diminished tumor burden in vivo. Our results expand the understanding of the critical role of metabolites in regulating cancer progression and antitumor immunity and open new avenues for developing novel therapeutic strategies against HCC.

DOI: https://doi.org/10.1038/s41418-024-01409-z
Int J Nanomedicine. 2024 ;19 12975-12998

A Novel Triptolide Nano-Liposome with Mitochondrial Targeting for Treatment of Hepatocellular Carcinoma.

Lili Zhou, Yang Du, Yating Shang, Debiao Xiang, Xinhua Xia.

   Background: Modern pharmacological studies have demonstrated that although triptolide (TP) is effective against hepatocellular carcinoma, it has poor water solubility and more toxic side effects. In this study, we used triptolide (TP), a bioactive constituent in Tripterygium wilfordii Hook F, as a model drug to develop a novel nano-liposome drug delivery system for the treatment of liver tumours.
Methods: We constructed a functionally-modified triptolide liposome (FA+TPP-TP-Lips) using the film-dispersion method and investigated its physicochemical properties, mitochondrial targeting of hepatic tumour cells, in vitro and in vivo anti-hepatic tumour activity and its mechanism.
Results: The prepared FA+TPP-TP-Lips had a particle size of 99.28 ± 5.7 nm, a PDI of 0.20 ± 0.02, a zeta potential of 1.2 ± 0.08 mV, and an encapsulation rate of 74.37% ± 1.07%.FA+TPP-TP-Lips facilitates the cellular uptake of drug delivery systems and improves their targeted delivery to mitochondria. The results of cell efficacy showed that FA+TPP-TP-Lips significantly inhibited the growth of liver cancer cells, decreased mitochondrial membrane potential, and increased intracellular ROS, thus enhancing the highest apoptosis rate of liver cancer cells. The targeted liposomes (FA-TP-Lips, TPP-TP-Lips, and FA+TPP-TP-Lips) had some degree of inhibitory migration effect on Huh-7 cells relative to the unmodified TP-Lips. Studies on tumor-bearing mice demonstrated that FA+ TPP-TP-Lips effectively accumulated in tumor tissues and significantly inhibited the growth of subcutaneous tumors, achieving a tumor inhibition rate of 79.37%. FA+ TPP-TP-Lips demonstrated an enhanced anti-liver tumor effect and significantly mitigated the hepatotoxicity and systemic toxicity associated with TP.
Conclusion: In summary, the results of this study can provide a feasible solution for improving the mitochondrial targeting of nano-liposomes, and lay a foundation for further developing a novel nano targeting preparation of triptolide for the treatment of hepatocellular carcinoma.

Keywords:  Folic acid; Hepatocellular Carcinoma; Mitochondrial Targeting; Triphenylphosphine ion; Triptolide

DOI:  https://doi.org/10.2147/IJN.S498099
Biol Pharm Bull. 2024 ;47(12): 1992-2002

Exploration of Novel Metabolic Features Reflecting Statin Sensitivity in Lung Cancer Cells.

Jiro Tashiro, Tomoko Warita, Akihiro Sugiura, Kana Mizoguchi, Takuro Ishikawa, Katsuhiko Warita.

  Statins are cholesterol-lowering drugs often used for the treatment of dyslipidemia. Statins also exert anti-cancer effects by inhibiting hydroxymethylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis. We previously reported that the susceptibility to statin treatment differs among cancer cells and that functional E-cadherin expression on the plasma membrane could be a biomarker of statin sensitivity in cancer cells. However, the detailed qualitative and molecular differences between statin-sensitive and statin-resistant cancer cells remain unclear. Here, we explored novel parameters related to statin sensitivity by comparing gene expression profiles and metabolite contents between statin-sensitive and statin-resistant lung cancer cell lines. We found that the expression of most cholesterol synthesis genes was lower in the statin-sensitive cancer cell line, HOP-92, than in the statin-resistant cancer cell line, NCI-H322M. Moreover, HOP-92 cells originally exhibited lower levels of CoA and HMG-CoA. Additionally, atorvastatin decreased the mRNA expression of PANK2, a rate-limiting enzyme in CoA synthesis. Atorvastatin also reduced the mRNA levels of the cholesterol esterification enzyme SOAT1, which was consistent with a decrease in the ratio of cholesterol ester to total cholesterol in HOP-92 cells. Our data suggest that the cholesterol synthetic flow and CoA content may be limited in statin-sensitive cancer cells. We also suggest that CoA synthesis and cholesterol storage may fluctuate with atorvastatin treatment in statin-sensitive cancer cells.

Keywords:  CoA; cancer; cholesterol; pantothenate kinase 2 (PANK2); statin sensitivity; sterol O-acyltransferase 1 (SOAT1)

DOI:  https://doi.org/10.1248/bpb.b24-00346
Theranostics. 2024 ;14(19): 7450-7469

Low PPP2R2A expression promotes sensitivity to CHK1 inhibition in high-grade serous ovarian cancer.

Zhaojun Qiu, Deepika Sigh, Yujie Liu, Chandra B Prasad, Nichalos Bean, Chunhong Yan, Zaibo Li, Xiaoli Zhang, Goutham Narla, Analisa DiFeo, Qi-En Wang, Junran Zhang.

Rationale: High-grade serous ovarian cancer (HGSOC), the most lethal epithelial ovarian cancer subtype, faces persistent challenges despite advances in the therapeutic use of PARP inhibitors. Thus, innovative strategies are urgently needed to improve survival rates for this deadly disease. Checkpoint kinase 1 (CHK1) is pivotal in regulating cell survival during oncogene-induced replication stress (RS). While CHK1 inhibitors (CHK1i's) show promise as monotherapy for ovarian cancer, a crucial biomarker for effective stratification in clinical trials is lacking, hindering efficacy improvement and toxicity reduction. PP2A B55α, encoded by PPP2R2A, is a regulatory subunit of the serine/threonine protein phosphatase 2 (PP2A) that influences CHK1 sensitivity in non-small cell lung cancer (NSCLC). Given the complexity of PP2A B55α function in different types of cancer, here we sought to identify whether PPP2R2A deficiency enhances the sensitivity of HGSOC to CHK1 inhibition. Methods: To determine whether PPP2R2A deficiency affects the sensitivity of HGSOC to CHK1 inhibition, we treated PPP2R2A knockdown (KD) HGSOC cells or HGSOC cells with naturally low PPP2R2A expression with a CHK1 inhibitor, then assessed cell growth in in vitro and in vivo assays. Additionally, we investigated the mechanisms contributing to the increased RS and the enhanced sensitivity to the CHK1 inhibitor in PPP2R2A-KD or deficient cells using various molecular biology assays, including western blotting, immunofluorescence, and DNA fiber assays. Results: Our study suggests that PPP2R2A-KD elevates c-Myc-induced RS via upregulation of replication initiation, rendering HGSOC cells reliant on CHK1 for survival, including those resistant to PARP inhibitors. Conclusion: Combined, these results identify PPP2R2A/PP2A B55α as a potential predictive biomarker for CHK1i sensitivity in HGSOC, as well as suggesting it as a therapeutic target to overcome PARP resistance.

DOI: https://doi.org/10.7150/thno.96879
bioRxiv. 2024 Nov 21. pii: 2024.11.20.624542. [Epub ahead of print]

Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma.

Navyateja Korimerla, Baharan Meghdadi, Isra Haq, Kari Wilder-Romans, Jie Xu, Nicole Becker, Ziqing Zhu, Peter Kalev, Nathan Qi, Charles Evans, Maureen Kachman, Zitong Zhao, Angelica Lin, Andrew J Scott, Alexandra O'Brien, Ayesha Kothari, Peter Sajjakulnukit, Li Zhang, Sravya Palavalasa, Erik R Peterson, Marc L Hyer, Katya Marjon, Taryn Sleger, Meredith A Morgan, Costas A Lyssiotis, Everett M Stone, Sean P Ferris, Theodore S Lawrence, Deepak Nagrath, Weihua Zhou, Daniel R Wahl.

Glioblastoma (GBM) is uniformly lethal due to profound treatment resistance. Altered cellular metabolism is a key mediator of GBM treatment resistance. Uptake of the essential sulfur-containing amino acid methionine is drastically elevated in GBMs compared to normal cells, however, it is not known how this methionine is utilized or whether it relates to GBM treatment resistance. Here, we find that radiation acutely increases the levels of methionine-related metabolites in a variety of treatment-resistant GBM models. Stable isotope tracing studies further revealed that radiation acutely activates methionine to S-adenosyl methionine (SAM) conversion through an active signaling event mediated by the kinases of the DNA damage response. In vivo tumor SAM synthesis increases after radiation, while normal brain SAM production remains unchanged, indicating a tumor- specific metabolic alteration to radiation. Pharmacological and dietary strategies to block methionine to SAM conversion slowed DNA damage response and increased cell death following radiation in vitro. Mechanistically, these effects are due to depletion of DNA repair proteins and are reversed by SAM supplementation. These effects are selective to GBMs lacking the methionine salvage enzyme methylthioadenosine phosphorylase. Pharmacological inhibition of SAM synthesis hindered tumor growth in flank and orthotopic in vivo GBM models when combined with radiation. By contrast, methionine depletion does not reduce tumor SAM levels and fails to radiosensitize intracranial models, indicating depleting SAM, as opposed to simply lowering methionine, is critical for hindering tumor growth in intracranial models of GBM. These results highlight a new signaling link between DNA damage and SAM synthesis and define the metabolic fates of methionine in GBM in vivo . Inhibiting radiation-induced SAM synthesis slows DNA repair and augments radiation efficacy in GBM. Using MAT2A inhibitors to deplete SAM may selectively overcome treatment resistance in GBMs with defective methionine salvage while sparing normal brain.

DOI: https://doi.org/10.1101/2024.11.20.624542
Oncogene. 2024 Dec 10.

Tissue factor promotes TREX1 protein stability to evade cGAS-STING innate immune response in pancreatic ductal adenocarcinoma.

Yinyin Xue, Yue Wang, Zhiqiang Ren, Ker Yu.

Pancreatic ductal adenocarcinoma (PDAC) remains the most challenging human malignancy that urgently needs effective therapy. Tissue factor (TF) is expressed in ~80% of PDAC and represents a potential therapeutic target. While a novel TF-ADC (MRG004A) demonstrated efficacy for PDAC and TNBC in a Phase I/II trial [Ref. 18], the functional role of TF in PDAC remains incompletely understood. We investigated the relationship between TF and the innate STING pathway. We found that patients with TF-overexpression had poor survival, very low levels of P-STING/P-TBK1, reduced amounts of ISGs and chemokines as well as low numbers of cytotoxic immunocytes in their tumor. In experimental models of mouse and human PDAC, tumor cell-intrinsic TF expression played a major role in silencing the cytosolic micronuclei sensing and cGAS-STING activation. This process involved a TREX1 exonuclease-dependent clearance of micronucleus-DNA accumulated in tumor cells. Treatment of tumors with TF-KO/shRNA or anti-TF antibody HuSC1-39 (parent antibody of MRG004A) triggered a rapid and proteasome-dependent degradation of TREX1 thereby restoring the STING/TBK1 cascade phosphorylation. TF-inhibition therapy promoted a robust STING/IRF3-dependent IFN/CCL5/CXCL9-11 production, immune effector cell infiltration and antitumor efficacy. Moreover, in the PBMC and cancer cell co-culture, TF-inhibition synergized with a STING agonist compound. A covalently conjugated TF antibody-STING agonist ADC strongly increased the efficacy of tumor-targeted STING agonism on chemokine secretion and tumor inhibition in vitro and in vivo. Thus, TF-inhibition reshapes an "immune hot" tumor environment. TF-targeted therapy warrants clinical investigation as a single agent or in combination with immunotherapy for treating TF-positive PDAC and TNBC.

DOI: https://doi.org/10.1038/s41388-024-03248-1
J Food Drug Anal. 2023 Aug 31. 31(3): 387-407

How to deal with frenemy NRF2: Targeting NRF2 for chemoprevention and cancer therapy.

Ya-Chu Tang, Yung-Jen Chuang, Hsin-Huei Chang, Shin-Hun Juang, Gow-Chin Yen, Jang-Yang Chang, Ching-Chuan Kuo.

Induction of antioxidant proteins and phase 2 detoxifying enzymes that neutralize reactive electrophiles are important mechanisms for protection against carcinogenesis. Normal cells provide multifaceted pathways to tightly control NF-E2-related factor 2 (NRF2)-mediated gene expression in response to an assault by a range of endogenous and exogenous oncogenic molecules. Transient activation of NRF2 by its activators is able to induce ARE-mediated cytoprotective proteins which are essential for protection against various toxic and oxidative damages, and NRF2 activators thereby have efficacy in cancer chemoprevention. Because NRF2 has a cytoprotective function, it can protect normal cells from carcinogens like an angel, but when the protective effect acts on cancer cells, it will give rise to invincible cancer cells and play a devilish role in tumor progression. Indeed, aberrant activation of NRF2 has been found in a variety of cancers that create a favorable environment for the proliferation and survival of cancer cells and leads to drug resistance, ultimately leading to the poor clinical prognosis of patients. Therefore, pharmacological inhibition of NRF2 signaling has emerged as a promising approach for cancer therapy. This review aims to compile the regulatory mechanisms of NRF2 and its double-edged role in cancer. In addition, we also summarize the research progress of NRF2 modulators, especially phytochemicals, in chemoprevention and cancer therapy.

DOI: https://doi.org/10.38212/2224-6614.3463
Apoptosis. 2024 Dec 10.

EFNA4-enhanced deubiquitination of SLC7A11 inhibits ferroptosis in hepatocellular carcinoma.

Xingyi Zhong, Zhiqin Zhu, Yangfeng Du, Lingzhi Long, Ziping Xie, Yangfeng Zhang, Huijun Yao, Junhao Lin, Fengsheng Chen.

  EFNA4, a member of the Ephrin-A ligand family, may influence hepatocellular carcinoma cells through two distinct mechanisms: one reliant on specific Eph receptor binding and the other independent of receptor involvement. However, EFNA4's influence on HCC via non-Eph receptor pathways remains unclear. In this study, we aimed to investigate the role of EFNA4 in a receptor-independent environment. Firstly, we constructed an environment lacking Eph receptors via CRISPR/Cas9 and found that EFNA4 could still partially promote HCC proliferation and metastasis in vivo and in vitro. Further analyses of apoptosis, ROS, and GPX4 expression revealed that overexpression of EFNA4 would inhibit ferroptosis in HCC. Mechanistically, EFNA4 was positively correlated with SLC7A11 and directly interacted with SLC7A11 in HCC via bioinformatics analysis. We demonstrated that the structural domain (a.a. 161-201) of EFNA4 specifically binds to the domain (a.a. 222-501) of SLC7A11, which led to the deubiquitination of SLC7A11. Subsequently, we found that EFNA4 would recruit the deubiquitinase USP9X, resulting in inhibition of SLC7A11 degradation, which ultimately inhibits ferroptosis and enhances the proliferation and metastasis of HCC. In conclusion, we demonstrated that EFNA4 promotes the proliferation and metastasis of HCC independent of Eph receptors by inhibiting ferroptosis and advancing the deubiquitination of SLC7A11 by recruiting the deubiquitinase USP9X. This indicates that EFNA4 could act as a potential prognostic marker and a prospective therapeutic target in patients with HCC.

Keywords:  Deubiquitination; EPHA2; Ephrin-A4; Ferroptosis; Hepatocellular carcinoma

DOI:  https://doi.org/10.1007/s10495-024-02042-4
Life Sci Alliance. 2025 Mar;pii: e202402912. [Epub ahead of print]8(3):

Mitochondrial signatures shape phenotype switching and apoptosis in response to PLK1 inhibitors.

Émilie Lavallée, Maëline Roulet-Matton, Viviane Giang, Roxana Cardona Hurtado, Dominic Chaput, Simon-Pierre Gravel.

PLK1 inhibitors are emerging anticancer agents that are being tested as monotherapy and combination therapies for various cancers. Although PLK1 inhibition in experimental models has shown potent antitumor effects, translation to the clinic has been hampered by low antitumor activity and tumor relapse. Here, we report the identification of mitochondrial protein signatures that determine the sensitivity to approaches targeting PLK1 in human melanoma cell lines. In response to PLK1 inhibition or gene silencing, resistant cells adopt a pro-inflammatory and dedifferentiated phenotype, whereas sensitive cells undergo apoptosis. Mitochondrial DNA depletion and silencing of the ABCD1 transporter sensitize cells to PLK1 inhibition and attenuate the associated pro-inflammatory response. We also found that nonselective inhibitors of the p90 ribosomal S6 kinase (RSK) exert their antiproliferative and pro-inflammatory effects via PLK1 inhibition. Specific inhibition of RSK, on the other hand, is anti-inflammatory and promotes a program of antigen presentation. This study reveals the overlooked effects of PLK1 on phenotype switching and suggests that mitochondrial precision medicine can help improve the response to targeted therapies.

DOI: https://doi.org/10.26508/lsa.202402912
Biomol Biomed. 2024 Dec 07.

miR-145-5p regulates hepatocellular carcinoma malignant advancement and immune escape via down-regulation of AcylCoA synthase ACSL4.

Dingxue Wang, Wenqi Huang, Gao Li.

Hepatocellular carcinoma (HCC) exhibits a subtle onset, high incidence rates, and low survival rates, becoming a substantial threat to human health. Hence, it is crucial to discover fresh biomarkers and treatment targets for the early detection and management of HCC. CCK-8, scratch-wound, and transwell assays were used to evaluate the biological properties of HCC cell lines (Huh-7 and Hep3B). Bioinformatics analysis identified the downstream target mRNA of miR-145-5p as acyl-CoA synthetase long-chain family member 4 (ACSL4). RT-qPCR was used to test miR-145-5p and ACSL4 levels. Transwell chambers were used to co-incubate purified CD8+ T cells and HCC cells for 48 h, and the effect of CD8+ T cells on apoptosis in HCC cells was detected by flow cytometry. A subcutaneous graft tumor model was constructed, and ELISA kits were used to assess cytokine levels and CD8+ T cell activation markers. HCC cells showed a decline in miR-145-5p levels and a rise in ACSL4 levels. Overexpression of miR-145-5p hindered HCC cell proliferation, migration, and invasion, while stimulating CD8+ T cell activation. Conversely, overexpression of ACSL4 enhanced the malignant biological properties of HCC cells and reduced the effect of CD8+ T cells, while silencing ACSL4 had the opposite effect. miR-145-5p targeted and downregulated ACSL4, while overexpression of miR-145-5p weakened the promotion of HCC malignant progression caused by ACSL4 overexpression. Additionally, overexpression of miR-145-5p and silencing ACSL4 were effective in inhibiting tumor growth in vivo. In conclusion, miR-145-5p targets and downregulates ACSL4, leading to the inhibition of HCC malignant progression and preventing immune escape in HCC cells.

DOI: https://doi.org/10.17305/bb.2024.11209
bioRxiv. 2024 Nov 26. pii: 2024.11.24.625107. [Epub ahead of print]

Autophagy inhibition induces AML cell death and enhances the efficacy of chemotherapy under hypoxia.

Eunice S Wang, Hannah R S Fay, Kaitlyn M Dykstra, Michael N Phelps, Matthew Johnson, Annemarie Harrigan, Marianna C Giorgi.

Outcomes of relapsed/refractory acute myeloid leukemia (AML) are poor, and strategies to improve outcomes are urgently needed. One important factor promoting relapse and chemoresistance is the ability of AML cells to thrive in vivo within an intrinsically hypoxic bone marrow microenvironment. Here we show that human AML cells exhibit enhanced autophagy, specifically mitophagy (i.e., increased accumulation of mitochondria and decreased mitochondrial membrane potential) under hypoxia. To target this pathway, we investigated the activity of the potent chloroquine-derived autophagy inhibitor, Lys05, on human AML cells, patient samples, and patient derived xenograft models. Inhibition of autophagy by Lys05 in AML cells prevented removal of damaged mitochondria and preferentially enhanced cell death under hypoxia mirroring the marrow microenvironment. Lys05 eradicated human AML cells of all genotypes including p53 mutant cells. Lys05 treatment in primary AML xenografted mice decreased CD34+CD38- human cells and prolonged overall survival. Moreover, Lys05 overcame hypoxia-induced chemoresistance and improved the efficacy of cytarabine, venetoclax, and azacytidine in vitro and in vivo in AML models. Our results demonstrate the importance of autophagy, specifically mitophagy, as a critical survival and chemoresistance mechanism of AML cells under hypoxic marrow conditions. Therapeutic targeting of this pathway in future clinical studies for AML is warranted.

DOI: https://doi.org/10.1101/2024.11.24.625107
Mol Carcinog. 2024 Dec 11.

HMGB3 Contributes to Anti-PD-1 Resistance by Inhibiting IFN-γ-Driven Ferroptosis in TNBC.

Bo Luo, Hongmei Zheng, Gai Liang, Yan Luo, Qu Zhang, Xiang Li.

  Our previous studies showed HMGB3 expression may correlate with immunotherapy efficacy in breast cancer patients. Here, we investigated whether HMGB3 overexpression has an impact on anti-PD-1 therapy in triple-negative breast cancer (TNBC) and its molecular mechanisms. Animal models were established to observe the effect of HMGB3 on sensitivity to anti-PD-1 treatment. Correlation of HMGB3 expression and ferroptosis preventive proteins in TNBC patients' tissues with anti-PD-1 therapy efficacy was analyzed. The impact of HMGB3 on IFN-γ (Interferon-gamma) inhibitory effects and signaling was examined in human TNBC cells where HMGB3 expression was knocked down using siRNA. Moreover, TNBC cells stably transfected with lentiviral vectors containing cDNA of HMGB3 were also used to confirm the effect of overexpression of HMGB3 on IFN-γ inhibitory effect and signaling. Effect of HMGB3 on IFN-γ-driven ferroptosis and ferroptosis-associated protein expression were also investigated. Correlation of HMGB3 and IRF1 and GPX4 expression in patient's cancer tissue were also investigated. Our results demonstrated that HMGB3 expression contributes to resistance to anti-PD-1 therapy in vivo. HMGB3 expression correlated with treatment efficacy of immunotherapy and survival in TNBC patients. HMGB3 silence decreased resistance of breast cancer cells to IFN-γ cytotoxic effect, while HMGB3 overexpression increased resistance of these cancer cells. HMGB3 silence increased STAT1 phosphorylation and IRF1 expression upon IFN-γ treatment compared with control. Overexpression of HMGB3 inhibited STAT1 phosphorylation and IFN-γ signaling in TNBC cells. Moreover, HMGB3 also increased STAT3 activation and had an effect of interaction between STAT1 and STAT3. HMGB3 overexpression decreased IFN-γ-driven ferroptosis in TNBC cells. HMGB3 increased ferroptosis-inhibitory proteins (SLC7A11, GPX4, and SLC3A2) expression in TNBC cells. Ferroptosis inhibition recovers resistance to anti-PD-1 therapy in vivo. Immunohistochemistry showed HMGB3 expression correlated with ferroptosis-associated proteins and IRF1 expression in breast cancer tissue. HMGB3 contributes to anti-PD-1 resistance by inhibiting IFN-γ-driven ferroptosis in TNBC which suggested HMGB3 is a potential co-target with anti-PD-1 therapy for TNBC.

Keywords:  HMGB3; IFN‐γ; breast cancer; ferroptosis; immunotherapy

DOI:  https://doi.org/10.1002/mc.23861
Front Immunol. 2024 ;15 1455741

Broadening horizons: the multifaceted role of ferroptosis in breast cancer.

Anqi Ge, Wang Xiang, Yan Li, Da Zhao, Junpeng Chen, Pawan Daga, Charles C Dai, Kailin Yang, Yexing Yan, Moujia Hao, Bolin Zhang, Wei Xiao.

  Breast cancer poses a serious threat to women's health globally. Current radiotherapy and chemotherapy regimens can induce drug-resistance effects in cancer tissues, such as anti-apoptosis, anti-pyroptosis, and anti-necroptosis, leading to poor clinical outcomes in the treatment of breast cancer. Ferroptosis is a novel programmed cell death modality characterized by iron overload, excessive generation of reactive oxygen species, and membrane lipid peroxidation. The occurrence of ferroptosis results from the imbalance between intracellular peroxidation mechanisms (executive system) and antioxidant mechanisms (defensive system), specifically involving iron metabolism pathways, amino acid metabolism pathways, and lipid metabolism pathways. In recent years, it has been found that ferroptosis is associated with the progression of various diseases, including tumors, hypertension, diabetes, and Alzheimer's disease. Studies have confirmed that triggering ferroptosis in breast cancer cells can significantly inhibit cancer cell proliferation and invasion, and improve cancer cell sensitivity to radiotherapy and chemotherapy, making induction of ferroptosis a potential strategy for the treatment of breast cancer. This paper reviews the development of the concept of ferroptosis, the mechanisms of ferroptosis (including signaling pathways such as GSH-GPX4, FSP1-CoQ1, DHODH-CoQ10, and GCH1-BH4) in breast cancer disease, the latest research progress, and summarizes the research on ferroptosis in breast cancer disease within the framework of metabolism, reactive oxygen biology, and iron biology. The key regulatory factors and mechanisms of ferroptosis in breast cancer disease, as well as important concepts and significant open questions in the field of ferroptosis and related natural compounds, are introduced. It is hoped that future research will make further breakthroughs in the regulatory mechanisms of ferroptosis and the use of ferroptosis in treating breast cancer cells. Meanwhile, natural compounds may also become a new direction for potential drug development targeting ferroptosis in breast cancer treatment. This provides a theoretical basis and opens up a new pathway for research and the development of drugs for the prevention and treatment of breast cancer.

Keywords:  breast cancer; ferroptosis; inflammation; iron metabolism; reactive oxygen species

DOI:  https://doi.org/10.3389/fimmu.2024.1455741
J Adv Res. 2024 Dec 06. pii: S2090-1232(24)00559-9. [Epub ahead of print]

Cancer-associated fibroblasts regulate mitochondrial metabolism and inhibit chemosensitivity via ANGPTL4-IQGAP1 axis in prostate cancer.

Zhi Xiong, Rui-Lin Zhuang, Shun-Li Yu, Zhao-Xiang Xie, Shi-Rong Peng, Ze-An Li, Bing-Heng Li, Jun-Jia Xie, Yi-Ning Li, Kai-Wen Li, Hai Huang.

   INTRODUCTION: Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment, being implicated in enhancing tumor growth and fostering drug resistance. Nonetheless, the mechanisms underlying their function in prostate cancer (PCa) remain incompletely understood, which is essential for devising effective therapeutic strategies.
OBJECTIVES: The main objective of this study was to explore the mechanisms by which CAFs mediate PCa growth and chemoresistance.
METHODS: We validated through data analysis and experimentation that CAFs significantly impact PCa cell proliferation and chemoresistance. Subsequently, we conducted a comprehensive proteomic analysis of the conditioned media from CAFs and PCa cells and identified angiopoietin-like protein 4 (ANGPTL4) as a key factor. We employed ELISA and multiplex immunofluorescence assays, all of which indicated that ANGPTL4 was primarily secreted by CAFs.Next, we conducted metabolomics analysis, GST pull-down assays, Co-IP, and other experiments to explore the specific molecular mechanisms of ANGPTL4 and its precise effects on PCa cells. Through drug screening, we identified Quercetin 3-O-(6'-galactopyranosyl)-β-D-galactopyranoside (QGGP) as an effective inhibitor of CAFs function. Finally, we thoroughly assessed the therapeutic potential of QGGP both as a monotherapy and in combination with docetaxel in PCa cells RESULTS: We discovered that the extracrine factor ANGPTL4 is primarily expressed in CAFs in PCa. When ANGPTL4 binds to IQ motif-containing GTPase-activating protein 1 (IQGAP1) on the PCa cell membrane, it activates the Raf-MEK-ERK-PGC1α axis, promoting mitochondrial biogenesis and OXPHOS metabolism, and thereby facilitating PCa growth and chemoresistance. Furthermore, virtual and functional screening strategies identified QGGP as a specific inhibitor of IQGAP1 that promotes its degradation. Combined with docetaxel treatment, QGGP can reverse the effects of CAFs and improve the responsiveness of PCa to chemotherapy.
CONCLUSIONS: This study uncovers a paracrine mechanism of chemoresistance in PCa and proposes that targeting the stroma could be a therapeutic choice.

Keywords:  ANGPTL4; Cancer-associated fibroblasts; Chemosensitivity; Mitochondria; Prostate cancer

DOI:  https://doi.org/10.1016/j.jare.2024.12.003
ACS Appl Mater Interfaces. 2024 Dec 12.

Polyanhydride Copolymer-Based Niclosamide Nanoparticles for Inhibiting Triple-Negative Breast Cancer: Metabolic Responses and Synergism with Paclitaxel.

Susheel Kumar Nethi, Siddhant Kothadiya, Brianna M White, Satyanarayana Rachagani, Rizia Bardhan, Surya K Mallapragada.

  The heterogeneity of tumors and the lack of effective therapies have resulted in triple-negative breast cancer (TNBC) exhibiting the least favorable outcomes among breast cancer subtypes. TNBC is characterized by its aggressive nature, often leading to high rates of relapse, metastasis, and mortality. Niclosamide (Nic), an Food and Drug Administration-approved anthelmintic drug, has been repurposed for cancer treatment; however, its application for TNBC is hindered by significant challenges, including strong hydrophobicity, poor aqueous solubility, and low bioavailability. This study aimed to develop Nic nanoparticles (Nic NPs) using biodegradable and biocompatible polyanhydride copolymers to enhance Nic's bioavailability and therapeutic efficacy. Nic NPs effectively inhibited migration, proliferation, and clonogenicity in both murine and human TNBC cells, inducing apoptosis and suppressing STAT3 signaling. For the first time, we utilized Raman spectroscopy and Seahorse extracellular flux assays to demonstrate the metabolic responses of TNBC cells to Nic NPs, revealing significant metabolic alterations, including the inhibition of mitochondrial respiration and glycolysis. Additionally, this study is the first to explore the combination therapy of repurposed Nic with the approved chemotherapeutic agent paclitaxel in the 4T1 TNBC immunocompetent mouse model. The combination of Nic NPs and paclitaxel significantly reduced tumor growth without adversely affecting the body weight of tumor-bearing mice. In summary, these findings suggest that Nic NPs could serve as a promising component in combination therapies for the effective treatment of TNBC.

Keywords:  drug repurposing; nanoparticles; niclosamide; polyanhydrides; spheroids; triple-negative breast cancer

DOI:  https://doi.org/10.1021/acsami.4c17961
Discov Immunol. 2024 ;3(1): kyae016

The sedoheptulose kinase CARKL controls T-cell cytokine outputs and migration by promoting metabolic reprogramming.

Michelangelo Certo, Jennifer Niven, Robert Haas, Paula Rudzinska, Joanne Smith, Danilo Cucchi, Jose R Hombrebueno, Claudio Mauro.

   Background: Immunometabolism is a crucial determinant of immune cell function, influencing cellular activation and differentiation through metabolic pathways. The intricate interplay between metabolism and immune responses is highlighted by the distinct metabolic programs utilized by immune cells to support their functions. Of particular interest is the pentose phosphate pathway (PPP), a key metabolic pathway branching out of glycolysis that plays a pivotal role in generating NADPH and pentose sugars crucial for antioxidant defense and biosynthesis. The sedoheptulose kinase Carbohydrate Kinase-like protein (CARKL), an enzyme involved in the PPP, emerges as a critical regulator of cell metabolism and was previously shown to play a role in macrophage function.
Methods: This study delves into the impact of CARKL expression on T-cell functionality, revealing dynamic alterations in response to cellular activation. Notably, CARKL overexpression leads to significant metabolic shifts in T cells, affecting mitochondrial respiration, ATP production, and inflammatory cytokine profiles. Furthermore, CARKL modulation influences T-cell motility by regulating chemokine receptor expression, particularly compromising CXCR3 expression and impairing T-cell migration in response to specific chemokine signals.
Conclusions: These findings underscore the multifaceted role of CARKL as a metabolic regulator shaping T-cell responses. Overall, our data reveal the complex regulatory mechanisms orchestrated by CARKL in T-cell function, with implications for immune regulation. Further exploration of the molecular interactions between CARKL and metabolic reprogramming in T cells could provide valuable insights into immune regulation and potential therapeutic strategies.

Keywords:  CARKL; T cells; immunometabolism; inflammation; pentose phosphate pathway; reprogramming

DOI:  https://doi.org/10.1093/discim/kyae016
Free Radic Biol Med. 2024 Dec 04. pii: S0891-5849(24)01108-0. [Epub ahead of print]227 201-209

Pleiotropic anti-cancer activities of novel non-covalent thioredoxin reductase inhibitors against triple negative breast cancer.

Brenna Flowers, Abigail Rullo, An Zhang, Keacha Chang, Valentina Z Petukhova, Sammy Y Aboagye, Francesco Angelucci, David L Williams, Steven Kregel, Pavel A Petukhov, Irida Kastrati.

Mounting evidence shows that tumor growth and progression rely on thioredoxin reductase 1 (TXNRD1)-mediated detoxification of oxidative stress that results from deregulated metabolism and mitogenic signaling in tumors. TXNRD1 levels are significant higher in triple negative breast cancer (TNBC) compared to normal tissue, making TXNRD1 a compelling TNBC therapeutic target. Despite the many attempts to generate TXNRD1 inhibitors, all known and reported compounds inhibiting TXNRD1 are problematic; they interact with TXNRD1 irreversibly and non-specifically resulting in numerous adverse side effects. Recently, a series of breakthrough studies identified a novel regulatory site, the 'doorstop pocket', in Schistosoma mansoni thioredoxin glutathione reductase, a TXNRD-like enzyme and an established drug target for the human parasitic infection, schistosomiasis. This discovery underpins the development of new first-in-class non-covalent inhibitors for this family of enzymes. Our data show that novel non-covalent TXNRD inhibitors (TXNRD(i)s) are potent dose-dependent inhibitors of viability in cellular models of TNBC. TXNRD(i)s attenuate several aggressive cancer phenotypes such as, clonogenic survival, mammosphere forming efficiency, invasion, and TXNRD-related gene expression in TNBC cells. TXNRD(i)s engage and inhibit TXNRD1 in live TNBC cells and xenograft tumors, thus supporting the mechanism of action at a cellular level. More importantly, TXNRD(i)s attenuated tumor growth in a preclinical MDA-MB-231 TNBC xenograft mouse model. Although additional optimization for TXNRD(i)s' potency is warranted, these results may open a new avenue for the development of novel small molecule therapeutics for TNBC.

DOI: https://doi.org/10.1016/j.freeradbiomed.2024.12.010