Rabeprazole has efficacy per se and reduces resistance to temozolomide in glioma via EMT inhibition

Autor:	Chandrashekhar Y. B. V. K, Phanithi Prakash Babu, Manas Panigrahi, Neera Yadav, Anwita Mudiraj, Deepak Babu
Rok vydání:	2021
Předmět:	Male 0301 basic medicine Cancer Research Epithelial-Mesenchymal Transition Cell Rabeprazole Vimentin Kaplan-Meier Estimate 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor Glioma Temozolomide Animals Humans Medicine Epithelial–mesenchymal transition Rats Wistar Antineoplastic Agents Alkylating biology Brain Neoplasms business.industry Cancer General Medicine Cadherins medicine.disease Gene Expression Regulation Neoplastic Disease Models Animal 030104 developmental biology medicine.anatomical_structure Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis embryonic structures Cancer research biology.protein Molecular Medicine Female business medicine.drug
Zdroj:	Cellular Oncology. 44:889-905
ISSN:	2211-3436 2211-3428
DOI:	10.1007/s13402-021-00609-w
Popis:	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. 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. 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. 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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5736cf5eb737161df86b6f7b6e8a2380 https://doi.org/10.1007/s13402-021-00609-w Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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