Control of HIF-1α Expression by eIF2α Phosphorylation–Mediated Translational Repression
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Abstract
Hypoxia inducible factor 1alpha (HIF-1alpha) plays a central role in regulating tumor angiogenesis via its effects on vascular endothelial growth factor (VEGF) transcription, and its expression is regulated through proteasome-mediated degradation. Paradoxically, previous studies have shown that proteasome inhibitors (PI) block tumor angiogensis by reducing VEGF expression, but the mechanisms have not been identified. Here, we report that PIs down-regulated HIF-1alpha protein levels and blocked HIF-1alpha transcriptional activity in human prostate cancer cells. PIs induced phosphorylation of the translation initiation factor 2alpha (eIF2alpha), which caused general translational repression to inhibit HIF-1alpha expression. Furthermore, PIs induced HIF-1alpha accumulation in LNCaP-Pro5 cells depleted of eIF2alpha via siRNA transfection and in MEFs expressing a phosphorylation-deficient mutant form of eIF2alpha. Finally, PIs failed to induce eIF2alpha phosphorylation or translational attenuation in DU145 or 253JB-V cells, and, in these cells, PIs promoted HIF-1alpha accumulation. Our data established that PIs down-regulated HIF-1alpha expression in cells that display activation of the unfolded protein response by stimulating phosphorylation of eIF2alpha and inhibiting HIF-1alpha translation.
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The counterintuitive effect of bortezomib arises from proteasome-independent mechanisms that primarily target HIF-1α synthesis, activation, and subcellular localization rather than protein degradation.
“Accumulating evidence indicates that this counterintuitive effect arises from proteasome-independent mechanisms that primarily target HIF-1α synthesis, activation, and subcellular localization rather than protein degradation [338,339].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [338]
The Introduction and Discussion report that bortezomib reduces HIF-1α translation and activity, explaining the paradoxical effect without invoking increased proteasomal degradation. The paper does not establish an effect on HIF-1α subcellular localization, and its Discussion does not establish that the mechanism is independent of proteasome inhibition. (LLM, conf=0.87)
Experimental — accuracy not yet measuredTranslational repression of HIF-1α is a key effect of bortezomib.
“This is consistent with earlier work identifying translational repression of HIF-1α as a key effect of bortezomib [338].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [338]
The Introduction reports that bortezomib inhibits HIF-1α translation, and the Discussion identifies translational downregulation as a mechanism of proteasome inhibitors. But the Introduction limits the finding to a subset of human prostate cancer cells; the Discussion also notes cell lines in which HIF-1α accumulated instead. Calling translational repression a key effect of bortezomib without that qualification overgeneralizes the finding. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTranslational repression of HIF-1α by bortezomib involves phosphorylation of eIF2α.
“translational repression of HIF-1α by bortezomib also involves phosphorylation of eukaryotic initiation factor-2α (eIF2α), a well-established mediator of stress-induced translational arrest [338].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [338]
Bortezomib is associated with suppression of HIF-1 signaling despite expectation that proteasome inhibition would stabilize HIF-α subunits.
“bortezomib, a clinically approved proteasome inhibitor used in multiple myeloma, has been repeatedly associated with suppression of HIF-1 signaling, despite the expectation that proteasome inhibition would stabilize HIF-α subunits [[336], [337], [338]].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [338]
Phosphorylation of eIF2α contributes to bortezomib-mediated repression of HIF-1α synthesis.
“Phosphorylation of eIF2α has been shown to contribute to bortezomib-mediated repression of HIF-1α synthesis, strengthening the interpretation that bortezomib exerts its effects largely through inhibition of HIF-1α protein synthesis.”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [338]
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“Accumulating evidence indicates that this counterintuitive effect arises from proteasome-independent mechanisms that primarily target HIF-1 α synthesis, activation, and subcellular localization rather than protein degradation [338,339].”
InfluentialProteotoxic Stress and Proteasome Inhibitor Efficacy and Resistance
McConkey, D. J. (2014) · Resistance to targeted anti-cancer therapeutics · doi:10.1007/978-3-319-06752-0_11
Self-citationProtein-protein interactions mediating hypoxia-inducible factor 1 complex function
Jagdeo, J. M. (2012) · Summit (Simon Fraser University)
Translation in Cancer at Hypoxia
Yi, T., & Wagner, G. (2014) · Springer eBooks · doi:10.1007/978-94-017-9078-9_20
Kuikel, K., McEwen, A., Mathiske, T. J., Wojtaszak, L., John, J. A. S., & Delbaz, A. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27198820
- Authors
- Zhu, K., Chan, W., Heymach, J., Wilkinson, M., & McConkey, D. J.
- Affiliations
- 1Cancer Biology, Departments of
- 3Biochemistry and Molecular Biology and
- The University of Texas MD Anderson Cancer Center (US)
- Venue
- Cancer Research
- Published
- 2009-03-01
- Volume
- 69
- Issue
- 5
- Pages
- 1836-1843
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4188393
- OpenAlex
- W1579227195
- Cited by
- 55
- References
- 39
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 3 · 2015: 4 · 2014: 7 · 2013: 5 · 2012: 3
- FWCI
- 2.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30CA016672)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- HIF-1α, eIF2α phosphorylation, protein synthesis inhibition, proteasome inhibitors, tumor angiogenesis, vascular endothelial growth factor, prostate cancer, unfolded protein response, HIF-1α stability, translation initiation factors
- MeSH terms
- Bortezomib, Endothelial PAS Domain-Containing Protein 1, Boronic Acids, Gene Expression Regulation, Humans, Lactones, Phosphorylation, Pyrazines, Pyrroles, RNA, Messenger, Protein Biosynthesis, Down-Regulation, Eukaryotic Initiation Factor-2, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Proteasome Endopeptidase Complex, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Proteasome Inhibitors
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