Dataset Information

MiR-634 sensitizes glioma cells to temozolomide by targeting CYR61 through Raf-ERK signaling pathway.

ABSTRACT: Glioma is the most common intracranial malignant tumors, accounting for about 40% of intracranial tumors. Primary or secondary drug resistance is one of the main reasons for the failure of treatment. The oncogenic or tumor-suppressive roles of miR-634 have been revealed in different types of cancer. However, the role of miR-634 in glioma remains unknown and whether miR-634 could sensitize glioma cells to temozolomide also is unclear. Here, we aim to investigate the biological function of miR-634 and the possible mechanisms in glioma. In this study, we found that miR-634 was downregulated in glioma tissues compared with normal brain tissues, and its expression was associated with tumor size and WHO grade. Importantly, glioma patients with low miR-634 expression showed a shorter survival time than patients which had high expression of miR-634. This study also showed that miR-634 was decreased in temozolomide-resistant glioma cells, and restoration of miR-634 could sensitize the resistant cells to temozolomide by targeting CYR61 through Raf-ERK signaling. Our study provides a potential target for overcome drug resistance in glioma.

SUBMITTER: Tan Z

PROVIDER: S-EPMC5852346 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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MiR-634 sensitizes glioma cells to temozolomide by targeting CYR61 through Raf-ERK signaling pathway.

Tan Zhigang Z Zhao Jizong J Jiang Yugang Y

Cancer medicine 20180223 3

Glioma is the most common intracranial malignant tumors, accounting for about 40% of intracranial tumors. Primary or secondary drug resistance is one of the main reasons for the failure of treatment. The oncogenic or tumor-suppressive roles of miR-634 have been revealed in different types of cancer. However, the role of miR-634 in glioma remains unknown and whether miR-634 could sensitize glioma cells to temozolomide also is unclear. Here, we aim to investigate the biological function of miR-634 ...[more]

PMID: 29473317

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Project description:Background:Intrinsic chemoresistance of glioblastoma (GBM) is frequently owed to activation of the PI3K and MEK/ERK pathways. These signaling cascades are tightly interconnected however the quantitative contribution of both to intrinsic resistance is still not clear. Here, we aimed at determining the activation status of these pathways in human GBM biopsies and cells and investigating the quantitative impact of both pathways to chemoresistance. Methods:Receptor tyrosine kinase (RTK) pathways in temozolomide (TMZ) treatment naive or TMZ resistant human GBM biopsies and GBM cells were investigated by proteome profiling and immunoblotting of a subset of proteins. Resistance to drugs and RTK pathway inhibitors was assessed by MTT assays. Apoptotic rates were determined by Annexin V staining and DNA damage with comet assays and immunoblotting. Results:We analyzed activation of RTK pathways by proteome profiling of tumor samples of patients which were diagnosed a secondary GBM and underwent surgery and patients which underwent a second surgery after TMZ treatment due to recurrence of the tumor. We observed substantial activation of the PI3K and MEK/ERK pathways in both groups. However, AKT and CREB phosphorylation was reduced in biopsies of resistant tumors while ERK phosphorylation remained unchanged. Subsequent proteome profiling revealed that multiple RTKs and downstream targets are also activated in three GBM cell lines. We then systematically describe a mechanism of resistance of GBM cell lines and human primary GBM cells to the alkylating drugs TMZ and cisplatin. No specific inhibitor of the upstream RTKs sensitized cells to drug treatment. In contrast, we were able to restore sensitivity to TMZ and cisplatin by inhibiting PI3K in all cell lines and in human primary GBM cells. Interestingly, an opposite effect was observed when we inhibited the MEK/ERK signaling cascade with two different inhibitors. Conclusions:Temozolomide treatment naive and TMZ resistant GBM biopsies show a distinct activation pattern of the MEK/ERK and PI3K signaling cascades indicating a role of these pathways in resistance development. Both pathways are also activated in GBM cell lines, however, only the PI3K pathway seems to play a crucial role in resistance to alkylating agents and might serve as drug target for chemosensitization.

Dataset Information

MiR-634 sensitizes glioma cells to temozolomide by targeting CYR61 through Raf-ERK signaling pathway.

Publications

MiR-634 sensitizes glioma cells to temozolomide by targeting CYR61 through Raf-ERK signaling pathway.

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