Mannose inhibits proliferation and promotes apoptosis to enhance sensitivity of glioma cells to temozolomide through Wnt/ß-catenin signaling pathway.

ABSTRACT

BACKGROUND: Temozolomide (TMZ) is generally applied for glioma treatment, while drug resistance of TMZ limits its therapeutic efficacy. Mannose exerts evident anti-tumor effect. We intended to investigate whether mannose enhanced TMZ sensitivity to glioma and examined the underlying mechanism. METHODS: MTT and clone formation assays were performed to detect cell viability and proliferation. Cell apoptosis was measured by flow cytometry. The protein and gene expression levels were detected by Western blot and qRT-PCR assays. Xenograft glioma model was established to explore the influence of mannose in vivo. RESULTS: Mannose inhibited glioma cell growth, which was facilitated by knockdown of phosphomannose isomerase (PMI) while reversed by overexpression of PMI. Mannose enhanced the sensitivity of glioma cells to TMZ, indicated by the further inhibited cell viability and colony formation and the aggravated cell apoptosis, which was reversed by overexpression of O6-methylguanine DNA methyltransferase (MGMT). Furthermore, mannose and TMZ inhibited MGMT expression and Wnt/ß-catenin activation. Moreover, activating Wnt/ß-catenin pathway blocked anti-proliferative effect induced by mannose and TMZ, which was further suppressed by overexpressed MGMT. Mannose inhibited glioma growth, suppressed Ki67 and downregulated MGMT and ß-catenin in vivo. CONCLUSION: Mannose inhibited MGMT to enhance sensitivity of glioma cells to TMZ, with Wnt/ß-catenin pathway involvement. Our data suggested that mannose could be an innovative agent to improve glioma treatment, particularly in TMZ-resistant glioma with high MGMT.