ArticlePloS one2009
Targeting hypoxia in cancer cells by restoring homeodomain interacting protein-kinase 2 and p53 activity and suppressing HIF-1alpha.
Article in PloS one, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 49 citations in OpenAlex.
- HIPK2 in Colon Cancer: A Potential Biomarker for Tumor Progression and Response to Therapies.International journal of molecular sciences · 2024Review
- The Sweet Side of HIPK2.Cancers · 2023Review
- HIPK2 in Angiogenesis: A Promising Biomarker in Cancer Progression and in Angiogenic Diseases.Cancers · 2023Review
- The Interplay Between Tumor Suppressor p53 and Hypoxia Signaling Pathways in Cancer.Frontiers in cell and developmental biology · 2021Review
- Regulation of the SIAH2-HIF-1 Axis by Protein Kinases and Its Implication in Cancer Therapy.Frontiers in cell and developmental biology · 2021Review
- Caveolin-1 scaffolding domain peptide regulates glucose metabolism in lung fibrosis.JCI insight · 2020Article
- Selective Inhibition of HIF1α Expression by ZnSOPathology oncology research : POR · 2020Article
- HIPK2 inhibits cell metastasis and improves chemosensitivity in esophageal squamous cell carcinoma.Experimental and therapeutic medicine · 2018Article
- Homeodomain-interacting protein kinase 2 (HIPK2): a promising target for anti-cancer therapies.Oncotarget · 2017Review
- Hyperglycemia triggers HIPK2 protein degradation.Oncotarget · 2017Article
- Zinc and zinc-containing biomolecules in childhood brain tumors.Journal of molecular medicine (Berlin, Germany) · 2016Review
- ZnCl2 sustains the adriamycin-induced cell death inhibited by high glucose.Cell death & disease · 2016Article
- Role of miR-27a, miR-181a and miR-20b in gastric cancer hypoxia-induced chemoresistance.Cancer biology & therapy · 2016Article
- Zn(II)-curc targets p53 in thyroid cancer cells.International journal of oncology · 2015Article
- The beneficial effect of Zinc(II) on low-dose chemotherapeutic sensitivity involves p53 activation in wild-type p53-carrying colorectal cancer cells.Journal of experimental & clinical cancer research : CR · 2015Article
- Verbascoside promotes apoptosis by regulating HIPK2-p53 signaling in human colorectal cancer.BMC cancer · 2014Article
- High glucose dephosphorylates serine 46 and inhibits p53 apoptotic activity.Journal of experimental & clinical cancer research : CR · 2014Article
- Degradation of mutant p53H175 protein by Zn(II) through autophagy.Cell death & disease · 2014Article
- A fluorescent curcumin-based Zn(II)-complex reactivates mutant (R175H and R273H) p53 in cancer cells.Journal of experimental & clinical cancer research : CR · 2013Article
- Zinc supplementation is required for the cytotoxic and immunogenic effects of chemotherapy in chemoresistant p53-functionally deficient cells.Oncoimmunology · 2013Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe tumor suppressor homeodomain-interacting protein kinase-2 (HIPK2) by phosphorylating serine 46 (Ser46) is a crucial regulator of p53 apoptotic function. HIPK2 is also a transcriptional co-repressor of hypoxia-inducible factor-1alpha (HIF-1alpha) restraining tumor angiogenesis and chemoresistance. HIPK2 can be deregulated in tumors by several mechanisms including hypoxia. Here, we sought to target hypoxia by restoring HIPK2 function and suppressing HIF-1alpha, in order to provide evidence for the involvement of both HIPK2 and p53 in counteracting hypoxia-induced chemoresistance. METHODOLOGY/PRINCIPAL
findingsUpon exposure of colon and lung cancer cells to hypoxia, by either low oxygen or cobalt, HIPK2 function was impaired allowing for increased HIF-1alpha expression and inhibiting the p53-apoptotic response to drug. Cobalt suppressed HIPK2 recruitment onto HIF-1alpha promoter. Hypoxia induced expression of the p53 target MDM2 that downregulates HIPK2, thus MDM2 inhibition by siRNA restored the HIPK2/p53Ser46 response to drug. Zinc supplementation to hypoxia-treated cells increased HIPK2 protein stability and nuclear accumulation, leading to restoration of HIPK2 binding to HIF-1alpha promoter, repression of MDR1, Bcl2, and VEGF genes, and activation of the p53 apoptotic response to drug. Combination of zinc and ADR strongly suppressed tumor growth in vivo by inhibiting HIF-1 pathway and upregulating p53 apoptotic target genes. CONCLUSIONS/SIGNIFICANCE: We show here for the first time that hypoxia-induced HIPK2 deregulation was counteracted by zinc that restored HIPK2 suppression of HIF-1 pathway and reactivated p53 apoptotic response to drug, underscoring the potential use of zinc supplementation in combination with chemotherapy to address hypoxia and improve tumor treatment.
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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.