bims-aspsyn 2025-07-27 papers

Carcinogenesis. 2025 Jul 20. pii: bgaf035. [Epub ahead of print]

GPS2 confers L-asparaginase resistance in acute lymphoblastic leukemia cells through ATF4/ASNS axis.

Jie Chen, Jili Luo, Yujie Liu, Jingjie Zhou, Hongjuan Cui, Longfei Deng.

L-asparaginase (L-ASP) is an important chemotherapeutic agent used in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, resistance to L-ASP is an unfavorable prognostic factor and the mechanism underlying L-ASP resistance is not fully understood. Here, we show that activation of the activating transcription factor 4 (ATF4) and induced expression of downstream target asparagine synthetase (ASNS) play a pivotal role in L-ASP resistance of ALL cells. In addition, the G protein pathway suppressor 2 (GPS2) binds to ATF4 and stabilizes ATF4 protein. Mechanistically, GPS2 inhibits ubiquitin-proteasome degradation of ATF4 through impairing the interaction between ATF4 and beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC), an E3 ligase that triggers proteasomal degradation of ATF4. Moreover, GPS2 knockdown sensitizes ALL cells to L-ASP treatment via repressing ATF4/ASNS axis in vitro and increases L-ASP efficacy against xenografted ALL tumors in vivo. Taken together, these findings demonstrate that GPS2 positively regulates ATF4/ASNS axis to confer L-ASP resistance in ALL cells, suggesting a therapeutic potential of targeting this pathway to overcome L-ASP resistance.

Keywords: ATF4; GPS2; L-asparaginase; acute lymphoblastic leukemia; resistance

DOI: https://doi.org/10.1093/carcin/bgaf035

Cancer Res Commun. 2025 Jul 23.

One-Carbon Metabolism Inhibition Depletes Purines and Results in Profound and Prolonged Ewing Sarcoma Growth Suppression.

Sara Zirpoli, Noah Copperman, Shrey Patel, Alexander Forrest, Zhanjun Hou, Larry H Matherly, David M Loeb, Antonio Di Cristofano.

Ewing sarcoma (EWS) is the second most common primary bone malignancy in adolescents and young adults. Patients who present with localized disease have experienced a steadily improving survival rate over the years, whereas those who present with metastatic disease have the same dismal prognosis as 30 years ago, with long term survival rates less than 20%, despite maximal intensification of chemotherapy. Thus, novel treatment approaches are a significant unmet clinical need. Targeting metabolic differences between EWS and normal cells offers a promising approach to improve outcomes for these patients. One-carbon metabolism utilizes serine and folate to generate glycine and tetrahydrofolate (THF)-bound one-carbon units required for de novo nucleotide biosynthesis. Elevated expression of several one-carbon metabolism genes is significantly associated with reduced survival in EWS patients. We show that both genetic and pharmacological inhibition of a key enzyme of the mitochondrial arm of the one-carbon metabolic pathway, serine hydroxymethyltransferase 2 (SHMT2), leads to substantial inhibition of EWS cell proliferation and colony-forming ability, and that this effect is primarily caused by depletion of glycine and one-carbon units required for synthesis of purine nucleotides. Inhibition of one-carbon metabolism at a different node, using the clinically relevant dihydrofolate reductase inhibitor Pralatrexate, similarly yields a profound growth inhibition, with depletion of thymidylate and purine nucleotides. Genetic depletion of SHMT2 dramatically impairs tumor growth in a xenograft model of EWS. Together, these data establish dependence on one-carbon metabolism as a novel and targetable vulnerability of EWS cells, which can be exploited for therapy.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0218

Sci Rep. 2025 Jul 18. 15(1): 26084

Inhibition of fatty acid binding protein suppresses pancreatic cancer progression and metastasis.

Shuhei Shinoda, Naohiko Nakamura, Kazuho Inoko, Mizuho Sato-Dahlman, Steven Carmella, Stephen Hecht, David A Bernlohr, Sayeed Ikramuddin, Masato Yamamoto.

Obesity is a known risk factor for Pancreatic ductal adenocarcinoma (PDAC). Fatty acid binding protein 4 (FABP4) is higher in plasma of obese patients, and linked to the progression of obesity-related cancers. To provide insights into the role of FABP4 in PDAC progression and determine the potential of FABP4 inhibitor for PDAC treatment, we elucidated the anticancer mechanism of FABP4 inhibition using FABP4 null mice and FABP4 inhibitor (HTS01037). In vitro, HTS010137 suppressed FABP4-induced cell viability in mouse (KPC cells) and human PDAC cell lines. FABP4 promoted invasive potency, epithelial-mesenchymal transition (EMT), and cancer stemness markers that were associated with up-regulation of transcription factor ZEB1. In vivo, both FABP4 knockout and inhibition with HTS01037 suppressed syngeneic KPC subcutaneous tumor growth with reduction of EMT and stemness and down-regulation of ZEB1. Human xenograft growth was also inhibited by HTS01037 treatment. In an orthotopic model, HTS01037 significantly suppressed tumor growth which improved distant metastases and survivals in mice. In liver metastasis mouse model, HTS01037 attenuated development and growth of liver metastases. Moreover, HTS01037 enhanced the efficacy of gemcitabine to PDAC. These findings indicate a promising translational value of FABP4 inhibitor as a critical therapeutic option in PDAC patients.

Keywords: Fatty acid binding protein 4; Metastasis; Obesity; Pancreatic ductal adenocarcinoma

DOI: https://doi.org/10.1038/s41598-025-11271-9

Blood. 2025 Jul 23. pii: blood.2024028069. [Epub ahead of print]

α-Ketoglutarate promotes amino acid depletion and suppresses B-cell lymphoma growth and development.

Carine Jaafar, Purushoth Ethiraj, Zhijun Qiu, An-Ping Lin, Pedro Simonis Seabra Martins Ferrari, Ricardo Aguiar.

Targeting metabolic dependencies and "starving" malignant cells have long been considered as potential strategies to treat cancer. However, with rare exceptions, the implementation of these maneuvers has been fraught with limited activity and lack of specificity. Multiple cytoplasmic and mitochondrial transaminases catalyze reactions that lead to amino acid catabolism. These enzymes use alpha-ketoglutarate (αKG) as a nitrogen acceptor, and accumulation of the competitive inhibitor metabolite D-2-HG perturbs their function. We postulated that exogenous αKG supplementation would influence the directionality of these reactions and deplete amino acids in cancer cells. Using B cell lymphoma as a model system, we found that αKG mediates a rapid and sustained amino acid depletion, principally of aspartate and branched-chain leucine, valine and isoleucine. The decrease in leucine levels influenced MTORC1 sub-cellular movement, suppressed its activity and associated with inhibition of B cell lymphoma growth in vitro and in vivo Increasing import of aspartate or leucine levels in the lymphoma cells, genetically forcing MTORC1 lysosomal localization or blocking leucine catabolism through BCAT2 deletion, all blunted the anti-lymphoma effects of αKG. In addition, long term dietary supplementation of αKG, a toxicity free strategy, significantly hindered lymphoma development in Eµ-Myc mice, in association with amino acid perturbation and impaired energy generation. We posit that αKG supplementation, which has been shown to improve health and lifespan in mice, also encodes marked anti-cancer properties.

DOI: https://doi.org/10.1182/blood.2024028069