Atypical induction of HIF-1α expression by pericellular Notch1 signaling suffices for the malignancy of glioblastoma multiforme cells

Abstract

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.

Deciphering the role of transcription factors in glioblastoma cancer stem cells

“…On the one hand, in line with the findings of Platet et al [108], HIF1α/HIF2α under hypoxic conditions induces the dedifferentiation of glioma cells into CSCs through Sox2 [4]. Under hypoxia, increased HIF-1α in GBM cells activates the HIF-1α-SERPINE1 pathway, JAK1/2-STAT3 pathway, and Notch signaling pathway, contributing to therapeutic resistance and malignancy [110,111]. Concurrently, targeted silencing of HIF-1α using siRNA can enhance the radiosensitivity of malignant gliomas [112].…”

Adult IDH Wild-Type Glioblastoma Ultrastructural Investigation Suggests a Possible Correlation between Morphological Biomarkers and Ki-67 Index

“…In this new nomenclature, the presence in glioblastoma of a mutation in the enzyme IDH is introduced, and the once-named glioblastoma grade IV is now defined as Glioblastoma IDH-wild type [62][63][64][65][66].…”

Tumor-suppressive function and mechanism of miR-873-5p in glioblastoma: evidence based on bioinformatics analysis and experimental validation

“…Meanwhile, amplified expression of HIF1α was noted in GBM brain tissues and cell lines; diminishing the expression of HIF1α leads to a decrease in U87MG cell viability [ 26 ]. In addition, inhibition of HIF1α can retard tumor development in a murine U251-xenograft model of GBM [ 27 ]. Another study has highlighted that the knockout of HIF1α in GBM cells eradicates cell invasion in vitro and inhibits tumor growth in vivo [ 28 ].…”