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Contact-based pericellular interactions play important roles in cancer progression via juxtacrine signaling pathways. The present study revealed that hypoxia-inducible factor-1α (HIF-1α), induced even in non-hypoxic conditions by cell-to-cell contact, was a critical cue responsible for the malignant characteristics of glioblastoma multiforme (GBM) cells through Notch1 signaling. Densely cultured GBM cells showed enhanced viability and resistance to temozolomide (TMZ) compared to GBM cells at a low density. Ablating Notch1 signaling by a γ-secretase inhibitor or siRNA transfection resensitized resistant GBM cells to TMZ treatment and decreased their viability under dense culture conditions. The expression of HIF-1α was significantly elevated in highly dense GBM cells even under non-hypoxic conditions. Atypical HIF-1α expression was associated with the Notch1 signaling pathway in both GBM and glioblastoma stem cells (GSC). Proteasomal degradation of HIF-1α was prevented by binding with Notch1 intracellular domain (NICD), which translocated to the nuclei of GBM cells. Silencing Notch1 signaling using a doxycycline-inducible Notch1 RNA-interfering system or treatment with chetomin, a HIF pathway inhibitor, retarded tumor development with a significant anti-cancer effect in a murine U251-xenograft model. Using GBM patient tissue microarray analysis, a significant increase in HIF-1α expression was identified in the group with Notch1 expression compared to the group without Notch1 expression among those with positive HIF-1α expression. Collectively, these findings highlight the critical role of cell-to-cell contact-dependent signaling in GBM progression. They provide a rationale for targeting HIF-1α signaling even in a non-hypoxic microenvironment.

Glutamate is an excitatory neurotransmitter distributed in the central nervous system of mammals. However, high concentrations of glutamate are known to cause neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and stroke by causing nerve cell death. In this study, the antioxidant activity and neuroprotective effect of subtropical natural products were analyzed. Among 11 subtropical plant extracts mainly tested, Sallacca wallichiana extract (SE) showed the greatest free radical scavenging activity. Then, we confirmed through WST-1 assay that SE protected HT22 cells against glutamate-induced cell death in a concentration-dependent manner. The protective effects of SE against glutamate-induced apoptosis in HT22 cells were also confirmed by flow cytometry analysis using Annexin V/PI double staining. We also confirmed using H 2 DCF-DA single staining that SE inhibits glutamate-induced intracellular reactive oxygen species. And we were confirmed through that SE inhibited glutamateinduced phosphorylation of Mitogen-activated Protein kinases. Consequently, our results propose that SE may contribute to the development of therapeutics to prevent neurodegenerative diseases.

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