PI3K-mTORC2 but not PI3K-mTORC1 regulates transcription of HIF2A/EPAS1 and vascularization in neuroblastoma
Published version of a preprint
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.
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Hypoxia-induced HIF2A transcription in neuroblastoma cells is highly dependent on PI3K-mTORC2 but not PI3K-mTORC1.
“We recently showed that hypoxia-induced HIF2A transcription in neuroblastoma cells is highly dependent on PI3K-mTORC2 but not PI3K-mTORC1, further supporting the hypothesis that targeting this pathway abrogates HIF activity (Mohlin et al., 2015).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Mohlin et al., 2015
SNS-derived tumors provide models to study HIF-2's role in tumorigenesis and metastasis and to test novel treatment protocols that target HIF-2 directly or indirectly by interfering with upstream or downstream pathways.
“Thus, these SNS-derived tumors provide models to study HIF-2's role in tumorigenesis and metastasis and to test novel treatment protocols that target HIF-2 directly or indirectly by interfering with upstream or downstream pathways (Richter et al., 2013;Mohlin et al., 2015).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Mohlin et al., 2015
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References 46 · Cited by 104
- Authors
- Mohlin, S., Hamidian, A., von Stedingk, K., Bridges, E., Wigerup, C., Bexell, D., & Påhlman, S.
- Affiliations
- Lund University (SE)
- 1Translational Cancer Research, Lund University Cancer Center at Medicon Village, Lund University, Lund, Sweden.
- University of Oxford (GB)
- Venue
- Cancer Research
- Published
- 2015-11-01
- Volume
- 75
- Issue
- 21
- Pages
- 4617-4628
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2099194731
- Cited by
- 104
- References
- 46
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 6 · 2023: 8 · 2022: 9 · 2021: 15 · 2020: 16 · 2019: 9 · 2018: 9 · 2017: 10 · 2016: 6
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- neuroblastoma, mTORC2, PI3K signaling, hypoxia, tumor angiogenesis, vascularization, IGF-1 receptor, insulin receptor, metastatic neuroblastoma, cancer stemness
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Regulatory-Associated Protein of mTOR, Mechanistic Target of Rapamycin Complex 2, Phosphoinositide-3 Kinase Inhibitors, Endothelial PAS Domain-Containing Protein 1, Animals, Female, Humans, Mice, Nude, Neovascularization, Pathologic, Neuroblastoma, Receptor, Insulin, RNA, Messenger, Transcription, Genetic, Signal Transduction, Antigens, CD, Gene Expression Regulation, Neoplastic, Receptors, Somatomedin, Receptor, IGF Type 1, Receptor, IGF Type 2, Phosphatidylinositol 3-Kinases, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-akt, Mice, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, TOR Serine-Threonine Kinases
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