Glutamine promotes escape from therapy-induced senescence in tumor cells

• DOI: 10.18632/aging.203495
• Publication Date: 2021-09-07T21:38:32Z
• Authors: Francesco Pacifico; Nadia Badolati; Stefano Mellone; Mariano Stornaiuolo; Antonio Leonardi; Elvira Crescenzi
• Keywords: cancer stem cells; Amino Acid Transport System ASC; 0301 basic medicine; Nitrogen; Glutamine; cancer stem cells; escape; glutamine; glutamine synthetase; therapy-induced senescence; A549 Cells; Amino Acid Transport System ASC; Cell Cycle Checkpoints; Cell Proliferation; Enzyme Activation; Glutamate-Ammonia Ligase; Glutamine; Humans; MCF-7 Cells; Minor Histocompatibility Antigens; Neoplasm Recurrence, Local; Neoplasms; Nitrogen; Nucleotides; Senescence-Associated Secretory Phenotype; Tumor Escape; Cellular Senescence; Neoplastic Stem Cells; Minor Histocompatibility Antigens; 03 medical and health sciences; Glutamate-Ammonia Ligase; Neoplasms; Humans; Cellular Senescence; Cell Proliferation; Nucleotides; glutamine synthetase; Cell Cycle Checkpoints; 3. Good health; Enzyme Activation; Neoplasm Recurrence; Local; A549 Cells; therapy-induced senescence; glutamine; MCF-7 Cells; Neoplastic Stem Cells; escape; Tumor Escape; Senescence-Associated Secretory Phenotype; Neoplasm Recurrence, Local; Research Paper

Therapy-induced senescence (TIS) is a major cellular response to anticancer therapies. While induction of a persistent growth arrest would be a desirable outcome in cancer therapy, it has been shown that, unlike normal cells, cancer cells are able to evade the senescence cell cycle arrest and to resume proliferation, likely contributing to tumor relapse. Notably, cells that escape from TIS acquire a plastic, stem cell-like phenotype. The metabolic dependencies of cells that evade senescence have not been thoroughly studied. In this study, we show that glutamine depletion inhibits escape from TIS in all cell lines studied, and reduces the stem cell subpopulation. In line with a metabolic reliance on glutamine, escaped clones overexpress the glutamine transporter SLC1A5. We also demonstrate a central role of glutamine synthetase that mediates resistance to glutamine deprivation, conferring independence from exogenous glutamine. Finally, rescue experiments demonstrate that glutamine provides nitrogen for nucleotides biosynthesis in cells that escape from TIS, but also suggest a critical involvement of glutamine in other metabolic and non-metabolic pathways. On the whole, these results reveal a metabolic vulnerability of cancer stem cells that recover proliferation after exposure to anticancer therapies, which could be exploited to prevent tumor recurrence.