Research Paper Volume 13, Issue 17 pp 20962—20991

Glutamine promotes escape from therapy-induced senescence in tumor cells

Francesco Pacifico1, , Nadia Badolati2, , Stefano Mellone1, , Mariano Stornaiuolo2, , Antonio Leonardi3, , Elvira Crescenzi1, ,

  • 1 Istituto di Endocrinologia ed Oncologia Sperimentale, CNR, Naples 80131, Italy
  • 2 Department of Pharmacy, University of Naples Federico II, Naples 80149, Italy
  • 3 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, University of Naples Federico II, Naples 80131, Italy

Received: February 12, 2021       Accepted: August 2, 2021       Published: September 7, 2021
How to Cite

Copyright: © 2021 Pacifico et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.


TIS: therapy-induced senescence; CSC: cancer stem cell-like; doxo: doxorubicin; cisPt: cisplatin; SA-β-gal: Senescence-associated beta-galactosidase; FBS: fetal bovine serum; BrdU: 5-bromo-2-deoxyuridine; PBS: phosphate-buffered saline; TCA cycle: tricarboxylic acid cycle; NAC: N-Acetyl-Cysteine; 2ME: β-Mercaptoethanol; NEAA: non-essential amino acids.