ArticlePloS one2015
The growth and aggressive behavior of human osteosarcoma is regulated by a CaMKII-controlled autocrine VEGF signaling mechanism.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 30 citations in OpenAlex.
- Review
- Hypoxia inducible factor-1ɑ as a potential therapeutic target for osteosarcoma metastasis.Frontiers in pharmacology · 2024Review
- Comprehensive analysis of the clinical significance and molecular mechanism of T-box transcription factor 3 in osteosarcoma.Journal of Cancer · 2024Article
- Advances in Intracellular Calcium Signaling Reveal Untapped Targets for Cancer Therapy.Biomedicines · 2021Review
- Up-regulation of pro-angiogenic molecules and events does not relate with an angiogenic switch in metastatic osteosarcoma cells but to cell survival features.Apoptosis : an international journal on programmed cell death · 2021Article
- Bioinformatics integrated analysis to investigate candidate biomarkers and associated metabolites in osteosarcoma.Journal of orthopaedic surgery and research · 2021Article
- TFAP2B, AP-1 and JAZF1 Expression in Tissues of Papillary Thyroid Carcinoma Patients; Clinical, Pathological and Prognostic Values.Asian Pacific journal of cancer prevention : APJCP · 2020Article
- Caveolin-1 Expression Together with VEGF can be a Predictor for Lung Metastasis and Poor Prognosis in Osteosarcoma.Pathology oncology research : POR · 2020Article
- Polymer-mediated gene therapy: Recent advances and merging of delivery techniques.Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology · 2020Review
- Article
- Article
- Expression of activator protein-1 in papillary thyroid carcinoma and its clinical significance.World journal of surgical oncology · 2019Article
- The Multi-Functional Calcium/Calmodulin Stimulated Protein Kinase (CaMK) Family: Emerging Targets for Anti-Cancer Therapeutic Intervention.Pharmaceuticals (Basel, Switzerland) · 2019Review
- Transcription factors regulate GPR91-mediated expression of VEGF in hypoxia-induced retinopathy.Scientific reports · 2017Article
- Human cytomegalovirus encoded chemokine receptor US28 activates the HIF-1α/PKM2 axis in glioblastoma cells.Oncotarget · 2016Article
- MicroRNA-20b Downregulates HIF-1α and Inhibits the Proliferation and Invasion of Osteosarcoma Cells.Oncology research · 2016Article
- CRISPR/Cas9: A revolutionary genome editing tool for human cancers treatment.Technology in cancer research & treatmentReview
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Osteosarcoma (OS) is a hyperproliferative malignant tumor that requires a high vascular density to maintain its large volume. Vascular Endothelial Growth Factor (VEGF) plays a crucial role in angiogenesis and acts as a paracrine and autocrine agent affecting both endothelial and tumor cells. The alpha-Ca2+/Calmodulin kinase two (α-CaMKII) protein is an important regulator of OS growth. Here, we investigate the role of α-CaMKII-induced VEGF in the growth and tumorigenicity of OS. We show that the pharmacologic and genetic inhibition of α-CaMKII results in decreases in VEGF gene expression (50%) and protein secretion (55%), while α- CaMKII overexpression increases VEGF gene expression (250%) and protein secretion (1,200%). We show that aggressive OS cells (143B) express high levels of VEGF receptor 2 (VEGFR-2) and respond to exogenous VEGF (100nm) by increasing intracellular calcium (30%). This response is ameliorated by the VEGFR inhibitor CBO-P11, suggesting that secreted VEGF results in autocrine stimulated α-CaMKII activation. Furthermore, we show that VEGF and α-CaMKII inhibition decreases the transactivation of the HIF-1α and AP-1 reporter constructs. Additionally, chromatin immunoprecipitation assay shows significantly decreased binding of HIF-1α and AP-1 to their responsive elements in the VEGF promoter. These data suggest that α-CaMKII regulates VEGF transcription by controlling HIF-1α and AP-1 transcriptional activities. Finally, CBO-P11, KN-93 (CaMKII inhibitor) and combination therapy significantly reduced tumor burden in vivo. Our results suggest that VEGF-induced OS tumor growth is controlled by CaMKII and dual therapy by CaMKII and VEGF inhibitors could be a promising therapy against this devastating adolescent disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.