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Inhibition of histamine receptor 3 suppresses glioblastoma tumor growth, invasion, and epithelial-to-mesenchymal transition.
- Source :
-
Oncotarget [Oncotarget] 2015 Jul 10; Vol. 6 (19), pp. 17107-20. - Publication Year :
- 2015
-
Abstract
- Histamine receptor 3 (H3R) is expressed in various tumors and correlated with malignancy and tumor proliferation. However, the role of H3R in tumor invasion and epithelial to mesenchymal transition (EMT) remains unknown. Here, we explored the H3R in the highly invasive glioblastoma (GBM) and U87MG cells. We found that H3R mRNA and protein levels were up-regulated in the GBM and glioma cell lines compared to normal brain tissue and astrocytes. In U87MG cell line, inhibition of H3R by siRNA or the antagonist ciproxifan (CPX) suppressed proliferation, invasiveness, and the expression of EMT activators (Snail, Slug and Twist). In addition, expression of epithelial markers (E-cadherin and ZO-1) was up-regulated and expression of mesenchymal markers (vimentin and N-cadherin) was down-regulated in vitro and in vivo in a xenograft model. In addition, we also showed that inhibition of H3R by siRNA or CPX inactivated the PI3K/Akt and MEK/ERK signaling pathways, while inhibition of Akt or ERK activity with antagonists or siRNAs suppressed H3R agonist (R)-(α)-(-)- methylhistamine dihydrobromide (RAMH) mediated invasion and reorganization of cadherin-household. In conclusion, overexpression of H3R is associated with glioma progression. Inhibition of H3R leads to suppressed invasion and EMT of GBM by inactivating the PI3K/Akt and MEK/ERK pathways in gliomas.
- Subjects :
- Animals
Blotting, Western
Cell Proliferation
Humans
Immunohistochemistry
Mice
Neoplasm Invasiveness pathology
Rats
Real-Time Polymerase Chain Reaction
Up-Regulation
Xenograft Model Antitumor Assays
Brain Neoplasms pathology
Epithelial-Mesenchymal Transition physiology
Glioblastoma pathology
Receptors, Histamine H3 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 6
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 25940798
- Full Text :
- https://doi.org/10.18632/oncotarget.3672