Abstract
Viral and pharmacological inducers of protein kinase RNA-activated (PKR)-like ER kinase (PERK) were shown to accelerate the phosphorylation- dependent degradation of the IFNAR1 chain of the Type 1 interferon (IFN) receptor and to limit cell sensitivity to IFN. Here we report that hypoxia can elicit these effects in a PERK-dependent manner. The altered fate of IFNAR1 affected by signaling downstream of PERK depends on phosphorylation of eIF2α (eukaryotic translational initiation factor 2-α) and ensuing activation of p38α kinase. Activators of other eIF2α kinases such as PKR or GCN2 (general control nonrepressed-2) are also capable of eliminating IFNAR1 and blunting IFN responses. Modulation of constitutive PKR activity in human breast cancer cells stabilizes IFNAR1 and sensitizes these cells to IFNAR1-dependent anti-tumorigenic effects. Although downregulation of IFNAR1 and impaired IFNAR1 signaling can be elicited in response to amino-acid deficit, the knockdown of GCN2 in melanoma cells reverses these phenotypes. We propose that, in cancer cells and the tumor microenvironment, activation of diverse eIF2α kinases followed by IFNAR1 downregulation enables multiple cellular components of tumor tissue to evade the direct and indirect anti-tumorigenic effects of Type 1 IFN.
| Original language | English |
|---|---|
| Pages (from-to) | 4214-4221 |
| Number of pages | 8 |
| Journal | Oncogene |
| Volume | 32 |
| Issue number | 36 |
| DOIs | |
| Publication status | Published - Sep 2013 |
| Externally published | Yes |
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Keywords
- GCN2
- IFNAR1
- integrated stress response
- interferon
- PERK
- tumor microenvironment
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics
Cite this
Anti-tumorigenic effects of Type 1 interferon are subdued by integrated stress responses. / Bhattacharya, S.; Huangfu, W. C.; Dong, G.; Qian, J.; Baker, D. P.; Karar, J.; Koumenis, C.; Diehl, J. A.; Fuchs, S. Y.
In: Oncogene, Vol. 32, No. 36, 09.2013, p. 4214-4221.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Anti-tumorigenic effects of Type 1 interferon are subdued by integrated stress responses
AU - Bhattacharya, S.
AU - Huangfu, W. C.
AU - Dong, G.
AU - Qian, J.
AU - Baker, D. P.
AU - Karar, J.
AU - Koumenis, C.
AU - Diehl, J. A.
AU - Fuchs, S. Y.
PY - 2013/9
Y1 - 2013/9
N2 - Viral and pharmacological inducers of protein kinase RNA-activated (PKR)-like ER kinase (PERK) were shown to accelerate the phosphorylation- dependent degradation of the IFNAR1 chain of the Type 1 interferon (IFN) receptor and to limit cell sensitivity to IFN. Here we report that hypoxia can elicit these effects in a PERK-dependent manner. The altered fate of IFNAR1 affected by signaling downstream of PERK depends on phosphorylation of eIF2α (eukaryotic translational initiation factor 2-α) and ensuing activation of p38α kinase. Activators of other eIF2α kinases such as PKR or GCN2 (general control nonrepressed-2) are also capable of eliminating IFNAR1 and blunting IFN responses. Modulation of constitutive PKR activity in human breast cancer cells stabilizes IFNAR1 and sensitizes these cells to IFNAR1-dependent anti-tumorigenic effects. Although downregulation of IFNAR1 and impaired IFNAR1 signaling can be elicited in response to amino-acid deficit, the knockdown of GCN2 in melanoma cells reverses these phenotypes. We propose that, in cancer cells and the tumor microenvironment, activation of diverse eIF2α kinases followed by IFNAR1 downregulation enables multiple cellular components of tumor tissue to evade the direct and indirect anti-tumorigenic effects of Type 1 IFN.
AB - Viral and pharmacological inducers of protein kinase RNA-activated (PKR)-like ER kinase (PERK) were shown to accelerate the phosphorylation- dependent degradation of the IFNAR1 chain of the Type 1 interferon (IFN) receptor and to limit cell sensitivity to IFN. Here we report that hypoxia can elicit these effects in a PERK-dependent manner. The altered fate of IFNAR1 affected by signaling downstream of PERK depends on phosphorylation of eIF2α (eukaryotic translational initiation factor 2-α) and ensuing activation of p38α kinase. Activators of other eIF2α kinases such as PKR or GCN2 (general control nonrepressed-2) are also capable of eliminating IFNAR1 and blunting IFN responses. Modulation of constitutive PKR activity in human breast cancer cells stabilizes IFNAR1 and sensitizes these cells to IFNAR1-dependent anti-tumorigenic effects. Although downregulation of IFNAR1 and impaired IFNAR1 signaling can be elicited in response to amino-acid deficit, the knockdown of GCN2 in melanoma cells reverses these phenotypes. We propose that, in cancer cells and the tumor microenvironment, activation of diverse eIF2α kinases followed by IFNAR1 downregulation enables multiple cellular components of tumor tissue to evade the direct and indirect anti-tumorigenic effects of Type 1 IFN.
KW - GCN2
KW - IFNAR1
KW - integrated stress response
KW - interferon
KW - PERK
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=84883741732&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84883741732&partnerID=8YFLogxK
U2 - 10.1038/onc.2012.439
DO - 10.1038/onc.2012.439
M3 - Article
C2 - 23045272
AN - SCOPUS:84883741732
VL - 32
SP - 4214
EP - 4221
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 36
ER -