RGD Reference Report - Oroxylin A increases the sensitivity of temozolomide on glioma cells by hypoxia-inducible factor 1α/hedgehog pathway under hypoxia. - Rat Genome Database

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Oroxylin A increases the sensitivity of temozolomide on glioma cells by hypoxia-inducible factor 1α/hedgehog pathway under hypoxia.

Authors: Wei, Mian  Ma, Rong  Huang, Shaoliang  Liao, Yan  Ding, Youxiang  Li, Zhaohe  Guo, Qinglong  Tan, Renxiang  Zhang, Lulu  Zhao, Li 
Citation: Wei M, etal., J Cell Physiol. 2019 Aug;234(10):17392-17404. doi: 10.1002/jcp.28361. Epub 2019 Feb 20.
RGD ID: 150573813
Pubmed: PMID:30790292   (View Abstract at PubMed)
DOI: DOI:10.1002/jcp.28361   (Journal Full-text)

Microenvironmental hypoxia-mediated drug resistance is responsible for the failure of cancer therapy. To date, the role of the hedgehog pathway in resistance to temozolomide (TMZ) under hypoxia has not been investigated. In this study, we discovered that the increasing hypoxia-inducible factor 1α (HIF-1α) activated the hedgehog pathway in hypoxic microenvironment by promoting autocrine secretion of sonic hedgehog protein (Shh), and then upregulating transfer of Gli1 to the nucleus, finally contributed to TMZ resistance in glioma cells. Oroxylin A (C16H12O5), a bioactive flavonoid, could induce HIF-1α degradation via prolyl-hydroxylases-VHL signaling pathway, resulting in the inactivation of the hedgehog. Besides, oroxylin A increased the expression of Sufu, which is a negative regulator of Gli1. By this mechanism, oroxylin A sensitized TMZ on glioma cells. U251 intracranial transplantation model and GL261 xenograft model were used to confirm the reversal effects of oroxylin A in vivo. In conclusion, our results demonstrated that HIF-1α/hedgehog pathway conferred TMZ resistance under hypoxia, and oroxylin A was capable of increasing the sensitivity of TMZ on glioma cells in vitro and in vivo by inhibiting HIF-1α/hedgehog pathway and depressing the activation of Gli1 directly.




  
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Original Reference(s)
SUFUHumanbrain glioblastoma multiforme  IEP human, rat, and/or mouse glioma cells in a mouse modelRGD 
SufuMousebrain glioblastoma multiforme  IEP human, rat, and/or mouse glioma cells in a mouse modelRGD 
SufuRatbrain glioblastoma multiforme  IEP human, rat, and/or mouse glioma cells in a mouse modelRGD 


  
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SUFUHumanoroxylin A  EXP oroxylin A increases the expression of Sufu in rat, mouse and human glioma cellsRGD 
SufuMouseoroxylin A  EXP oroxylin A increases the expression of Sufu in rat, mouse and human glioma cellsRGD 
SufuRatoroxylin A  EXP oroxylin A increases the expression of Sufu in rat, mouse and human glioma cellsRGD 


Biological Process

  
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SufuRatpositive regulation of cellular response to drug  IEP  RGD 


Genes (Rattus norvegicus)
Sufu  (SUFU negative regulator of hedgehog signaling)

Genes (Mus musculus)
Sufu  (SUFU negative regulator of hedgehog signaling)

Genes (Homo sapiens)
SUFU  (SUFU negative regulator of hedgehog signaling)