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Published on: October 27, 2014
Rabeprazole has efficacy per se and reduces resistance to temozolomide in glioma via EMT inhibition
Deepak Babu1, Anwita Mudiraj1, Neera Yadav1
1Neuro Science Laboratory, Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, 500 046, Telangana State, India.
Purpose:
Epithelial to mesenchymal transition (EMT) is pivotal in embryonic development and wound healing, whereas in cancer it inflicts malignancy and drug resistance. The recognition of an EMT-like process in glioma is relatively new and its clinical and therapeutic significance has, as yet, not been fully elucidated. Here, we aimed to delineate the clinical significance of the EMT-like process in glioma and its therapeutic relevance to rabeprazole.
Methods:
We investigated the expression profiles of EMT-associated proteins in primary glioma biopsies through Western blotting and immunohistochemistry, and correlated them with various clinicopathological features and data listed in the cancer genome atlas (TCGA). In addition, the anticancer efficacy of rabeprazole and its therapeutic relevance to EMT along with temozolomide chemo-sensitization were assessed using multiple cell-based assays, Western blotting and confocal imaging. For in vivo assessment, we used a stereotaxic C6-rat glioma model.
Results:
Expression analysis of EMT-associated proteins in glioma biopsies, in conjunction with clinicopathological and TCGA dataset analyses, revealed non-canonical expression of E/N-cadherin and upregulation of GFAP, vimentin and β-catenin. The increased expression of EMT-associated proteins may attribute to glioma malignancy and a poor patient prognosis. Subsequent in vitro studies revealed that rabeprazole treatment attenuated glioma cell growth and migration, and induced apoptosis. Rabeprazole suppressed EMT by impeding AKT/GSK3β phosphorylation and/or NF-κB signaling and sensitized temozolomide resistance. Additional in vivo studies showed restricted tumor growth and inhibited expression of EMT-associated proteins after rabeprazole treatment.
Conclusions:
Our data revealed (i) a clinical association of the EMT-like process with glioma malignancy and a poor survival and (ii) an anticancer and temozolomide sensitizing effect of rabeprazole by repressing EMT.
Insights
The epithelial to mesenchymal transition (EMT)-like process in glioma is linked to malignancy and poor prognosis. Rabeprazole shows anticancer effects by inhibiting EMT and enhancing temozolomide efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Epithelial to mesenchymal transition (EMT) is crucial for development but drives cancer malignancy and drug resistance.
- The role of EMT-like processes in glioma is emerging, with limited understanding of its clinical and therapeutic implications.
Purpose of the Study:
- To investigate the clinical significance of EMT-like processes in glioma.
- To explore the therapeutic potential of rabeprazole in glioma, focusing on its impact on EMT and chemosensitization.
Main Methods:
- Western blotting and immunohistochemistry analyzed EMT-associated proteins in glioma biopsies.
- TCGA data correlated EMT markers with clinicopathological features.
- In vitro and in vivo models assessed rabeprazole's efficacy, EMT inhibition, and temozolomide chemosensitization.
Main Results:
- Glioma biopsies showed non-canonical E/N-cadherin expression and elevated GFAP, vimentin, and β-catenin, correlating with malignancy and poor prognosis.
- Rabeprazole reduced glioma cell growth, migration, and induced apoptosis.
- Rabeprazole suppressed EMT by inhibiting AKT/GSK3β and NF-κB signaling, overcoming temozolomide resistance.
Conclusions:
- The EMT-like process is clinically associated with glioma malignancy and reduced patient survival.
- Rabeprazole exhibits anticancer activity and enhances temozolomide effectiveness by repressing EMT in glioma.
