Cellular senescence or EGFR signaling induces Interleukin 6 (IL-6) receptor expression controlled by mammalian target of rapamycin (mTOR)

Cell Cycle. 2013 Nov 1;12(21):3421-32. doi: 10.4161/cc.26431. Epub 2013 Sep 18.

Abstract

Interleukin 6 (IL-6) signaling plays a role in inflammation, cancer, and senescence. Here, we identified soluble IL-6 receptor (sIL-6R) as a member of the senescence-associated secretory phenotype (SASP). Senescence-associated sIL-6R upregulation was mediated by mammalian target of rapamycin (mTOR). sIL-6R was mainly generated by a disintegrin and metalloprotease 10 (ADAM10)-dependent ectodomain shedding to enable IL-6 trans-signaling. In vivo, heterozygous PTEN-knockout mice exhibited higher mTOR activity and increased sIL-6R levels. Moreover, aberrant EGF receptor (EGFR) activation triggered IL-6 synthesis. In analogy to senescence, EGFR-induced activation of mTOR also induced IL-6R expression and sIL-6R generation. Hence, mTOR activation reprograms IL-6 non-responder cells into IL-6 responder cells. Our data suggest that mTOR serves as a central molecular switch to facilitate cellular IL-6 classic and trans-signaling via IL-6R upregulation with direct implications for cellular senescence and tumor development.

Keywords: EGFR; Interleukin 6; Interleukin 6-Receptor; SASP; mTOR; senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism
  • ADAM10 Protein
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cellular Senescence / genetics
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism
  • Fetal Proteins / antagonists & inhibitors
  • Fetal Proteins / genetics
  • Fetal Proteins / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Interleukin-6 / genetics*
  • Interleukin-6 / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / antagonists & inhibitors
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • PTEN Phosphohydrolase / deficiency
  • PTEN Phosphohydrolase / genetics
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, Interleukin-6 / genetics*
  • Receptors, Interleukin-6 / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Carrier Proteins
  • Fetal Proteins
  • Interleukin-6
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • RNA, Small Interfering
  • Receptors, Interleukin-6
  • TACC3 protein, mouse
  • mTOR protein, mouse
  • EGFR protein, mouse
  • ErbB Receptors
  • TOR Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • ADAM10 Protein
  • Adam10 protein, mouse