Browsing by Subject "Tumor metabolism"

Now showing 1 - 4 of 4
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    Asparagine, a critical limiting metabolite during glutamine starvation
    (Taylor & Francis, 2018-04-11) Jiang, Jie; Pavlova, Natalya N.; Zhang, Ji; Pediatrics, School of Medicine
    A challenge of targeting glutamine metabolism in cancer is that tumor cells develop various strategies to adapt to glutamine limitation. We found that asparagine plays a critical role in supporting protein synthesis during glutamine starvation, highlighting a possible approach to optimize the therapeutic efficacy of targeting glutamine metabolism in cancer.
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    Potential therapies targeting nuclearmetabolic regulation in cancer
    (Wiley, 2023-11-29) Chen, Yanjie; Xu, Jie; Liu, Xiaoyi; Guo, Linlin; Yi, Ping; Cheng, Chunming; Microbiology and Immunology, School of Medicine
    The interplay between genetic alterations and metabolic dysregulation is increasingly recognized as a pivotal axis in cancer pathogenesis. Both elements are mutually reinforcing, thereby expediting the ontogeny and progression of malignant neoplasms. Intriguingly, recent findings have highlighted the translocation of metabolites and metabolic enzymes from the cytoplasm into the nuclear compartment, where they appear to be intimately associated with tumor cell proliferation. Despite these advancements, significant gaps persist in our understanding of their specific roles within the nuclear milieu, their modulatory effects on gene transcription and cellular proliferation, and the intricacies of their coordination with the genomic landscape. In this comprehensive review, we endeavor to elucidate the regulatory landscape of metabolic signaling within the nuclear domain, namely nuclear metabolic signaling involving metabolites and metabolic enzymes. We explore the roles and molecular mechanisms through which metabolic flux and enzymatic activity impact critical nuclear processes, including epigenetic modulation, DNA damage repair, and gene expression regulation. In conclusion, we underscore the paramount significance of nuclear metabolic signaling in cancer biology and enumerate potential therapeutic targets, associated pharmacological interventions, and implications for clinical applications. Importantly, these emergent findings not only augment our conceptual understanding of tumoral metabolism but also herald the potential for innovative therapeutic paradigms targeting the metabolism–genome transcriptional axis.
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    PRMT1 promotes pancreatic cancer development and resistance to chemotherapy
    (Elsevier, 2024) Ku, Bomin; Eisenbarth, David; Baek, Seonguk; Jeong, Tae-Keun; Kang, Ju-Gyeong; Hwang, Daehee; Noh, Myung-Giun; Choi, Chan; Choi, Sungwoo; Seol, Taejun; Kim, Yun-Hee; Woo, Sang Myung; Kong, Sun-Young; Lim, Dae-Sik; Medicine, School of Medicine
    Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer, and novel treatment regimens are direly needed. Epigenetic regulation contributes to the development of various cancer types, but its role in the development of and potential as a therapeutic target for PDAC remains underexplored. Here, we show that PRMT1 is highly expressed in murine and human pancreatic cancer and is essential for cancer cell proliferation and tumorigenesis. Deletion of PRMT1 delays pancreatic cancer development in a KRAS-dependent mouse model, and multi-omics analyses reveal that PRMT1 depletion leads to global changes in chromatin accessibility and transcription, resulting in reduced glycolysis and a decrease in tumorigenic capacity. Pharmacological inhibition of PRMT1 in combination with gemcitabine has a synergistic effect on pancreatic tumor growth in vitro and in vivo. Collectively, our findings implicate PRMT1 as a key regulator of pancreatic cancer development and a promising target for combination therapy.
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    Promoter demethylation of the asparagine synthetase gene is required for ATF4-dependent adaptation to asparagine depletion
    (Elsevier, 2019-12-06) Jiang, Jie; Srivastava, Sankalp; Seim, Gretchen; Pavlova, Natalya N.; King, Bryan; Zou, Lihua; Zhang, Chi; Zhong, Minghua; Feng, Hui; Kapur, Reuben; Wek, Ronald C.; Fan, Jing; Zhang, Ji; Pediatrics, School of Medicine
    Tumor cells adapt to nutrient-limited environments by inducing gene expression that ensures adequate nutrients to sustain metabolic demands. For example, during amino acid limitations, ATF4 in the amino acid response induces expression of asparagine synthetase (ASNS), which provides for asparagine biosynthesis. Acute lymphoblastic leukemia (ALL) cells are sensitive to asparagine depletion, and administration of the asparagine depletion enzyme l-asparaginase is an important therapy option. ASNS expression can counterbalance l-asparaginase treatment by mitigating nutrient stress. Therefore, understanding the mechanisms regulating ASNS expression is important to define the adaptive processes underlying tumor progression and treatment. Here we show that DNA hypermethylation at the ASNS promoter prevents its transcriptional expression following asparagine depletion. Insufficient expression of ASNS leads to asparagine deficiency, which facilitates ATF4-independent induction of CCAAT-enhancer-binding protein homologous protein (CHOP), which triggers apoptosis. We conclude that chromatin accessibility is critical for ATF4 activity at the ASNS promoter, which can switch ALL cells from an ATF4-dependent adaptive response to ATF4-independent apoptosis during asparagine depletion. This work may also help explain why ALL cells are most sensitive to l-asparaginase treatment compared with other cancers.