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PI3K-mTORC2 but not PI3K-mTORC1 Regulates Transcription of HIF2A/EPAS1 and Vascularization in Neuroblastoma.

Mohlin, Sofie LU ; Hamidian, Arash LU ; von Stedingk, Kristoffer LU ; Bridges, Esther; Wigerup, Caroline LU ; Bexell, Daniel LU and Påhlman, Sven LU (2015) In Cancer Research 75(21). p.4617-4628
Abstract
Hypoxia-inducible factor (HIF) is a master regulator of cellular responses to oxygen deprival with a critical role in mediating the angiogenic switch in solid tumors. Differential expression of the HIF subunits HIF1α and HIF2α occurs in many human tumor types, suggesting selective implications to biologic context. For example, high expression of HIF2α that occurs in neuroblastoma is associated with stem cell-like features, disseminated disease, and poor clinical outcomes, suggesting pivotal significance for HIF2 control in neuroblastoma biology. In this study, we provide novel insights into how HIF2α expression is transcriptionally controlled by hypoxia and how this control is abrogated by inhibition of insulin-like growth... (More)
Hypoxia-inducible factor (HIF) is a master regulator of cellular responses to oxygen deprival with a critical role in mediating the angiogenic switch in solid tumors. Differential expression of the HIF subunits HIF1α and HIF2α occurs in many human tumor types, suggesting selective implications to biologic context. For example, high expression of HIF2α that occurs in neuroblastoma is associated with stem cell-like features, disseminated disease, and poor clinical outcomes, suggesting pivotal significance for HIF2 control in neuroblastoma biology. In this study, we provide novel insights into how HIF2α expression is transcriptionally controlled by hypoxia and how this control is abrogated by inhibition of insulin-like growth factor-1R/INSR-driven phosphoinositide 3-kinase (PI3K) signaling. Reducing PI3K activity was sufficient to decrease HIF2α mRNA and protein expression in a manner with smaller and less vascularized tumors in vivo. PI3K-regulated HIF2A mRNA expression was independent of Akt or mTORC1 signaling but relied upon mTORC2 signaling. HIF2A mRNA was induced by hypoxia in neuroblastoma cells isolated from metastatic patient-derived tumor xenografts, where HIF2A levels could be reduced by treatment with PI3K and mTORC2 inhibitors. Our results suggest that targeting PI3K and mTORC2 in aggressive neuroblastomas with an immature phenotype may improve therapeutic efficacy. Cancer Res; 75(21); 1-12. ©2015 AACR. (Less)
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organization
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type
Contribution to journal
publication status
published
subject
in
Cancer Research
volume
75
issue
21
pages
4617 - 4628
publisher
American Association for Cancer Research Inc.
external identifiers
  • pmid:26432405
  • wos:000365602200019
  • scopus:84946593823
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-15-0708
language
English
LU publication?
yes
id
7b588b59-09af-485b-a522-22f10fd3023a (old id 8158995)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26432405?dopt=Abstract
date added to LUP
2015-11-02 17:00:53
date last changed
2017-11-12 03:02:02
@article{7b588b59-09af-485b-a522-22f10fd3023a,
  abstract     = {Hypoxia-inducible factor (HIF) is a master regulator of cellular responses to oxygen deprival with a critical role in mediating the angiogenic switch in solid tumors. Differential expression of the HIF subunits HIF1α and HIF2α occurs in many human tumor types, suggesting selective implications to biologic context. For example, high expression of HIF2α that occurs in neuroblastoma is associated with stem cell-like features, disseminated disease, and poor clinical outcomes, suggesting pivotal significance for HIF2 control in neuroblastoma biology. In this study, we provide novel insights into how HIF2α expression is transcriptionally controlled by hypoxia and how this control is abrogated by inhibition of insulin-like growth factor-1R/INSR-driven phosphoinositide 3-kinase (PI3K) signaling. Reducing PI3K activity was sufficient to decrease HIF2α mRNA and protein expression in a manner with smaller and less vascularized tumors in vivo. PI3K-regulated HIF2A mRNA expression was independent of Akt or mTORC1 signaling but relied upon mTORC2 signaling. HIF2A mRNA was induced by hypoxia in neuroblastoma cells isolated from metastatic patient-derived tumor xenografts, where HIF2A levels could be reduced by treatment with PI3K and mTORC2 inhibitors. Our results suggest that targeting PI3K and mTORC2 in aggressive neuroblastomas with an immature phenotype may improve therapeutic efficacy. Cancer Res; 75(21); 1-12. ©2015 AACR.},
  author       = {Mohlin, Sofie and Hamidian, Arash and von Stedingk, Kristoffer and Bridges, Esther and Wigerup, Caroline and Bexell, Daniel and Påhlman, Sven},
  issn         = {1538-7445},
  language     = {eng},
  number       = {21},
  pages        = {4617--4628},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {PI3K-mTORC2 but not PI3K-mTORC1 Regulates Transcription of HIF2A/EPAS1 and Vascularization in Neuroblastoma.},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-15-0708},
  volume       = {75},
  year         = {2015},
}