The unfolded protein response controls induction and activation of ADAM17/TACE by severe hypoxia and ER stress

Abstract

The family of ADAM (a disintegrin and metalloproteinase) proteins has been implicated in tumor initiation and progression. ADAM17/tumor necrosis factor-a (TNFa)-converting enzyme (TACE) has been initially recognized to release TNFa as well as its receptors (TNFRs) from the membrane. ADAM17, TNFa and TNFR have been found upregulated in cancer patients, although the underlying mechanisms remain largely unknown. As hypoxia is a hallmark of cancer that can lead to severe stress conditions accumulating in endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), we investigated the role of these stress conditions in the regulation of ADAM17 and release of TNFR1.We found that severe hypoxia induced ADAM17 expression and activity. Although hypoxia-inducible factor 1a (HIF1a) was important to maintain basal ADAM17 mRNA levels during moderate hypoxia, it was not sufficient to induce ADAM17 levels under severe hypoxia. Instead, we found that ADAM17 induction by severe hypoxia can be mimicked by ER stressors such as Thapsigargin and occurs as a consequence of the activation of the PERK/eIF2a/ATF4 and activating transcription factor 6 (ATF6) arms of UPR in several tumor cell lines. ADAM17 expression was also increased in xenografts displaying ER stress because of treatment with the vascular endothelial growth factor (VEGF) inhibitory antibody Bevacizumab. Additionally, severe hypoxia and ER stress activated ADAM17 and ectodomain shedding of TNFR1 involving mitogen-activated protein (MAP) kinases and reactive oxygen species (ROS). Collectively, these results show that ADAM17 is a novel UPRregulated gene in response to severe hypoxia and ER stress, which is actively involved in the release of TNFR1 under these conditions. These data provide a novel link between severe hypoxic stress conditions and inflammation in the tumor environment.

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

“…This includes shedding processes of membrane associated factors like the TNFR1 in severe hypoxia but also vesicular membrane trafficking. 47 Hypoxia affects for example vesicular trafficking of ion channels. 48 A recent report indicates moreover that for glutamate receptor trafficking hypoxia and the PHD2 homolog Egln-9 play a fundamental role in Caenorhabditis elegans.…”

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

“…PERK-mediated activation of ATF4 leads to the increase of proangiogenic factors such as VEGF, FGF2, and IL-6 and to the decrease in antiangiogenic factors THBS1, CXCL14, and CXCL10 in a HIF1a-independent manner (43). The PERK and ATF6 arms of the UPR also induce ADAM17, a member of the ADAM (a disintegrin and metalloproteinase) family that is associated with tumor initiation and progression (75). In other brain tumors such as medulloblastoma, PERK activation increases VEGFA expression and is associated with enhanced cell migration through VEGFR2 signaling (76).…”

Abrogation of ER stress-induced apoptosis of alveolar epithelial cells by angiotensin 1–7

“…By analogy, the findings reported in Fig. 9 strongly suggest that the general mechanism of ADAM17-induced ACE-2 ectodomain shedding might occur in lung fibrogenesis in response to various stimuli that could include viral infection, mutant proteins, or even hyperoxic gas (18), each of which would be compelling topics for further inquiry. In addition, the finding that TAPI-2 also reduced the active forms of cathepsin D (Fig.…”