Upregulation of HIF-1α protects neuroblastoma cells from hypoxia-induced apoptosis in a RhoA-dependent manner
Open accessAbstract
Hypoxic conditions regulate several metabolic enzymes and transcription factors that are involved in cancer, ischemia and pulmonary diseases. The Ras homolog (Rho) family, including Rho member A (RhoA), is involved in reorganization of the actin cytoskeleton, cell migration and in the regulation of apoptosis and gene transcription. The aim of the present study was to investigate the expression of hypoxia‑inducible factor (HIF)‑α and the activity of RhoA in PC12 neuroblastoma cells under hypoxic conditions. The upregulation of HIF‑α and RhoA by hypoxia was determined using reverse transcription‑quantitative polymerase chain reaction and western blot assays, cell apoptosis was analyzed using flow cytometry, and the activity of caspase 3 was examined using a western blot assay and caspase 3 activity assay kit. The PC12 cells were induced to apoptosis following exposure to hypoxia, and exhibited increased expression of HIF‑α and increased mRNA and protein expression levels of RhoA. The overexpression of HIF‑α attenuated the hypoxia‑induced apoptosis of the PC12 cells. In addition, RhoA knockdown using small interfering RNA abrogated the antagonism of HIF‑1α towards hypoxia‑induced apoptosis. The results of the present study confirmed the protective role of HIF‑1α and RhoA in hypoxia‑induced PC12 cell apoptosis, and that the upregulation of HIF‑1α by hypoxia is RhoA‑dependent.
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HIF-1α transcriptional activation of RHOA has consistently been reported across a number of different cell types, including breast cancer cells, cardiac myocytes, neuroblastoma cells, mesenchymal stem cells, and chondrocytes.
“In contrast, HIF-1α transcriptional activation of RHOA has consistently been reported across a number of different cell types, including breast cancer cells [87], cardiac myocytes [88], neuroblastoma cells [89], mesenchymal stem cells [90], and chondrocytes [91].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [89]
The cited paper’s ‘Hypoxia induces RhoA in PC12 cells’ section reports that hypoxia increased RhoA expression in neuroblastoma cells. Its RhoA-knockdown experiment found that reducing RhoA reduced hypoxia-induced HIF-1α expression—the opposite regulatory direction from the claimed HIF-1α activation of RHOA. The paper does not establish HIF-1α transcriptional activation of RHOA. (LLM, conf=0.85)
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Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
Kaelin, W. G., & Ratcliffe, P. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.04.009 · Cited by 3,251 · cited 1× · see citing works
“Following activation by hypoxia, the HIF-1 α /HIF-1 β dimmer (19) binds to a conserved DNA consensus on the promoters of its target genes, known as the hypoxia-responsive element (20,21), and induces a group of gene products that are crucial for hypoxic adaptation (22).”
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- Whiteley W, Tseng MC and Sandercock P: Blood biomarkers in the diagnosis of ischemic stroke: A systematic review. Stroke 39: 2902-2909, 2008.
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RhoA Signaling in Neurodegenerative Diseases
Schmidt, S. I., Blaabjerg, M., Freude, K., & Meyer, M. (2022) · Cells · doi:10.3390/cells11091520 · Cited by 110 · see citing works
- Authors
- YIN, C.-P., GUAN, S.-H., ZHANG, B., WANG, X.-X., & YUE, S.-W.
- Affiliations
- Dongyang People's Hospital (CN)
- Yuhuangding Hospital (CN)
- ORCID
- ZHANG, BO
- Venue
- Molecular Medicine Reports
- Publisher
- Spandidos Publications
- Published
- 2015-08-28
- Volume
- 12
- Issue
- 5
- Pages
- 7123-7131
- ISSN
- 1791-2997 (ISSN-L)
- 1791-3004
- OpenAlex
- W1897544395
- Cited by
- 9
- References
- 1
- Citations by year
- 2026: 1 · 2024: 1 · 2022: 1 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 1
- FWCI
- 0.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Medicine Reports (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Shandong University
- Qilu Hospital of Shandong University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Keywords
- HIF-1α, RhoA, hypoxia, apoptosis, neuroblastoma, PC12 cells, caspase-3, Rho GTPases, hypoxia-induced cell death
- MeSH terms
- Animals, Neuroblastoma, Poly(ADP-ribose) Polymerases, RNA, Messenger, Cell Hypoxia, Up-Regulation, Apoptosis, rhoA GTP-Binding Protein, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Rats, Hypoxia-Inducible Factor 1, alpha Subunit, Caspase 3, Real-Time Polymerase Chain Reaction
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