bims-polyam Biomed News
on Polyamines
Issue of 2023–06–11
three papers selected by
Sebastian J. Hofer, University of Graz
  1. Hypusination Maintains Intestinal Homeostasis and Prevents Colitis and Carcinogenesis by Enhancing Aldehyde Detoxification.
  2. Tumor cell-derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8+ T cell activation.
  3. The positive effect of spermidine in older adults suffering from dementia after 1 year.
  1. Gastroenterology. 2023 Jun 02. pii: S0016-5085(23)00814-4. [Epub ahead of print]
    Hypusination Maintains Intestinal Homeostasis and Prevents Colitis and Carcinogenesis by Enhancing Aldehyde Detoxification.
    Alain P Gobert, Thaddeus M Smith, Yvonne L Latour, Mohammad Asim, Daniel P Barry, Margaret M Allaman, Kamery J Williams, Kara M McNamara, Alberto G Delgado, Sarah P Short, Raghavendra G Mirmira, Kristie L Rose, Kevin L Schey, Irene Zagol-Ikapitte, Jeremy S Coleman, Olivier Boutaud, Shilin Zhao, M Blanca Piazuelo, M Kay Washington, Lori A Coburn, Keith T Wilson.
       BACKGROUND & AIMS: The amino acid hypusine, synthesized from the polyamine spermidine by the enzyme deoxyhypusine synthase (DHPS), is essential for the activity of eukaryotic translation initiation factor 5A (EIF5A). The role of hypusinated EIF5A (EIF5AHyp) remains unknown in intestinal homeostasis. Our aim was to investigate EIF5AHyp in the gut epithelium in inflammation and carcinogenesis.
    METHODS: We utilized human colon tissue mRNA samples and publicly-available transcriptomic datasets, tissue microarrays, and patient-derived colon organoids. Mice with intestinal epithelial-specific deletion of Dhps were investigated at baseline and in models of colitis and colon carcinogenesis.
    RESULTS: We found that patients with ulcerative colitis and Crohn's disease exhibit reduced colon levels of DHPS mRNA and DHPS protein, and reduced levels of EIF5AHyp. Similarly, colonic organoids from colitis patients also show downregulated DHPS expression. Mice with intestinal epithelial-specific deletion of Dhps develop spontaneous colon hyperplasia, epithelial proliferation, crypt distortion, and inflammation. Furthermore, these mice are highly susceptible to experimental colitis and show exacerbated colon tumorigenesis when treated with a carcinogen. Transcriptomic and proteomic analysis on colonic epithelial cells demonstrated that loss of hypusination induces multiple pathways related to cancer and immune response. Moreover, we found that hypusination enhances translation of numerous enzymes involved in aldehyde detoxification, including glutathione S-transferases and aldehyde dehydrogenases. Accordingly, hypusination-deficient mice exhibit increased levels of aldehyde adducts in the colon, and their treatment with a scavenger of electrophiles reduces colitis.
    CONCLUSIONS: Hypusination in intestinal epithelial cells has a key role in prevention of colitis and colorectal cancer, and enhancement of this pathway via supplementation of spermidine could have therapeutic impact.
    Keywords:  Colon cancer; Hypusine; Inflammation; Intestinal epithelial cells
    DOI:  https://doi.org/10.1053/j.gastro.2023.05.041
  2. Proc Natl Acad Sci U S A. 2023 Jun 13. 120(24): e2305245120
    Tumor cell-derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8+ T cell activation.
    Sana Hibino, Shotaro Eto, Sho Hangai, Keiko Endo, Sanae Ashitani, Maki Sugaya, Tsuyoshi Osawa, Tomoyoshi Soga, Tadatsugu Taniguchi, Hideyuki Yanai.
      The activation and expansion of T cells that recognize cancer cells is an essential aspect to antitumor immunity. Tumors may escape destruction by the immune system through ectopic expression of inhibitory immune ligands typically exemplified by the PD-L1/PD-1 pathway. Here, we reveal another facet of tumor evasion from T cell surveillance. By secretome profiling of necrotic tumor cells, we identified an oncometabolite spermidine as a unique inhibitor of T cell receptor (TCR) signaling. Mechanistically, spermidine causes the downregulation of the plasma membrane cholesterol levels, resulting in the suppression of TCR clustering. Using syngeneic mouse models, we show that spermidine is abundantly detected in the tumor immune microenvironment (TIME) and that administration of the polyamine synthesis inhibitor effectively enhanced CD8+ T cell-dependent antitumor responses. Further, the combination of the polyamine synthesis inhibitor with anti-PD-1 immune checkpoint antibody resulted in a much stronger antitumor immune response. This study reveals an aspect of immunosuppressive TIME, wherein spermidine functions as a metabolic T cell checkpoint that may offer a unique approach for promoting tumor immunotherapy.
    Keywords:  T cell; cancer immunotherapy; cell death; oncometabolite; spermidine
    DOI:  https://doi.org/10.1073/pnas.2305245120
  3. Wien Klin Wochenschr. 2023 Jun 07.
    The positive effect of spermidine in older adults suffering from dementia after 1 year.
    Thomas Pekar, Aribert Wendzel, Reinhart Jarisch.
       BACKGROUND: A positive effect of the effect of a 3-month oral spermidine intake on memory performance has already been demonstrated. The continuation of this study aimed to examine whether there could be observed an improvement in memory performance after one year.
    METHOD: 45 residents of the nursing home "Gepflegt Wohnen" in Hart bei Graz, Styria, Austria, were given a daily dose of 3.3 mg spermidine in their diet for one year.
    RESULTS: The comparison of the MMSE test results at baseline and after one year demonstrated a significant (p < 0.001) difference. The mean improvement is 5 points.
    CONCLUSION: The new results confirm the already proven positive effect of oral spermidine intake on memory performance.
    Keywords:  Alzheimer; Biogen amines; CERAD-Plus; Memory perfomance; Nutrition
    DOI:  https://doi.org/10.1007/s00508-023-02226-z
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