bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2021–09–26
two papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Interleukin-6 mediates PSAT1 expression and serine metabolism in TSC2-deficient cells.
  2. Supply and demand: Cellular nutrient uptake and exchange in cancer.
  1. Proc Natl Acad Sci U S A. 2021 09 28. pii: e2101268118. [Epub ahead of print]118(39):
    Interleukin-6 mediates PSAT1 expression and serine metabolism in TSC2-deficient cells.
    Ji Wang, Harilaos Filippakis, Thomas Hougard, Heng Du, Chenyang Ye, Heng-Jia Liu, Long Zhang, Khadijah Hindi, Shefali Bagwe, Julie Nijmeh, John M Asara, Wei Shi, Souheil El-Chemaly, Elizabeth P Henske, Hilaire C Lam.
      Tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM) are caused by aberrant mechanistic Target of Rapamycin Complex 1 (mTORC1) activation due to loss of either TSC1 or TSC2 Cytokine profiling of TSC2-deficient LAM patient-derived cells revealed striking up-regulation of Interleukin-6 (IL-6). LAM patient plasma contained increased circulating IL-6 compared with healthy controls, and TSC2-deficient cells showed up-regulation of IL-6 transcription and secretion compared to wild-type cells. IL-6 blockade repressed the proliferation and migration of TSC2-deficient cells and reduced oxygen consumption and extracellular acidification. U-13C glucose tracing revealed that IL-6 knockout reduced 3-phosphoserine and serine production in TSC2-deficient cells, implicating IL-6 in de novo serine metabolism. IL-6 knockout reduced expression of phosphoserine aminotransferase 1 (PSAT1), an essential enzyme in serine biosynthesis. Importantly, recombinant IL-6 treatment rescued PSAT1 expression in the TSC2-deficient, IL-6 knockout clones selectively and had no effect on wild-type cells. Treatment with anti-IL-6 (αIL-6) antibody similarly reduced cell proliferation and migration and reduced renal tumors in Tsc2 +/- mice while reducing PSAT1 expression. These data reveal a mechanism through which IL-6 regulates serine biosynthesis, with potential relevance to the therapy of tumors with mTORC1 hyperactivity.
    Keywords:  interleukin 6; lymphangioleiomyomatosis; mTORC1; phosphoserine aminotransferase 1 (PSAT1); tuberous sclerosis complex
    DOI:  https://doi.org/10.1073/pnas.2101268118
  2. Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00693-6. [Epub ahead of print]81(18): 3731-3748
    Supply and demand: Cellular nutrient uptake and exchange in cancer.
    Vasileios Papalazarou, Oliver D K Maddocks.
      Nutrient supply and demand delineate cell behavior in health and disease. Mammalian cells have developed multiple strategies to secure the necessary nutrients that fuel their metabolic needs. This is more evident upon disruption of homeostasis in conditions such as cancer, when cells display high proliferation rates in energetically challenging conditions where nutritional sources may be scarce. Here, we summarize the main routes of nutrient acquisition that fuel mammalian cells and their implications in tumorigenesis. We argue that the molecular mechanisms of nutrient acquisition not only tip the balance between nutrient supply and demand but also determine cell behavior upon nutrient limitation and energetic stress and contribute to nutrient partitioning and metabolic coordination between different cell types in inflamed or tumorigenic environments.
    Keywords:  SLC proteins; amino acid; cancer; nutrient scavenging; nutrient transport; nutrient transporters
    DOI:  https://doi.org/10.1016/j.molcel.2021.08.026
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