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<p>Growing evidence suggests that the proapoptotic TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5) signaling pathway can also trigger the production of inflammatory cytokines, thereby promoting tumor progression. We recently reported that glutamine depletion impacts the survival of glutamine-dependent tumor cells by activating the TRAIL-R2/DR5-mediated apoptotic machinery. However, it remains unclear whether glutamine limitation activates a TRAIL-R2/DR5-regulated inflammatory response. In this study, we demonstrate that glutamine starvation activates two parallel signaling pathways, leading to the gene expression and secretion of the pro-angiogenic and pro-inflammatory interleukin-8 (IL-8/CXCL8) in tumor cells. Our findings reveal that the amino acid-sensing general control nonderepressible-2 kinase (GCN2)/activating transcription factor 4 (ATF4) signaling axis contributes to the upregulation of IL-8 gene expression in glutamine-deprived tumor cells. Furthermore, our results indicate that the loss of the long isoform of cellular FLICE-inhibitory protein (cFLIP<sub>L</sub>), which occurs as result of the metabolic stress induced by glutamine limitation, promotes TRAIL-independent activation of the NF-kB pathway via TRAIL-R2/DR5, a key mechanism driving the observed IL-8 upregulation under starvation conditions. Given the severe depletion of glutamine observed in growing tumors, our data suggest that IL-8 secretion, induced by this metabolic stress, may play a significant role in activating inflammatory and angiogenic responses, thereby counteracting apoptosis and ultimately promoting tumor progression.</p>

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Activation of the integrated stress response and loss of cFLIPL under glutamine limitation induce IL-8 gene expression and secretion in glutamine-dependent tumor cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月19日

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  • Rocío Mora-Molina,
  • F. Javier Fernández-Farrán,
  • Abelardo López-Rivas,
  • Carmen Palacios

摘要

Growing evidence suggests that the proapoptotic TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5) signaling pathway can also trigger the production of inflammatory cytokines, thereby promoting tumor progression. We recently reported that glutamine depletion impacts the survival of glutamine-dependent tumor cells by activating the TRAIL-R2/DR5-mediated apoptotic machinery. However, it remains unclear whether glutamine limitation activates a TRAIL-R2/DR5-regulated inflammatory response. In this study, we demonstrate that glutamine starvation activates two parallel signaling pathways, leading to the gene expression and secretion of the pro-angiogenic and pro-inflammatory interleukin-8 (IL-8/CXCL8) in tumor cells. Our findings reveal that the amino acid-sensing general control nonderepressible-2 kinase (GCN2)/activating transcription factor 4 (ATF4) signaling axis contributes to the upregulation of IL-8 gene expression in glutamine-deprived tumor cells. Furthermore, our results indicate that the loss of the long isoform of cellular FLICE-inhibitory protein (cFLIPL), which occurs as result of the metabolic stress induced by glutamine limitation, promotes TRAIL-independent activation of the NF-kB pathway via TRAIL-R2/DR5, a key mechanism driving the observed IL-8 upregulation under starvation conditions. Given the severe depletion of glutamine observed in growing tumors, our data suggest that IL-8 secretion, induced by this metabolic stress, may play a significant role in activating inflammatory and angiogenic responses, thereby counteracting apoptosis and ultimately promoting tumor progression.