Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells

Franziska Puschel, Francesca Favaro, Jaime Redondo-Pedraza, Estefania Lucendo, Raffaella Iurlaro, Sandrine Marchetti, Blanca Majem, Eric Eldering, Ernest Nadal, Jean-Ehrland Ricci, Eric Chevet, Cristina Muñoz-Pinedo

Research output: Contribution to journalArticleAcademicpeer-review

59 Citations (Scopus)

Abstract

Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation.
Original languageEnglish
Pages (from-to)9932-9941
Number of pages10
JournalPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume117
Issue number18
DOIs
Publication statusPublished - 5 May 2020

Keywords

  • Cancer immunity
  • Cancer metabolism
  • Cytokines
  • Glucose

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