The Notch Target Hes1 Directly Modulates Gli1 Expression and Hedgehog Signaling: A Potential Mechanism of Therapeutic Resistance

Abstract

Purpose: Multiple developmental pathways including Notch, Hedgehog, and Wnt are active in malignant brain tumors such as medulloblastoma and glioblastoma (GBM). This raises the possibility that tumors might compensate for therapy directed against one pathway by upregulating a different one. We investigated whether brain tumors show resistance to therapies against Notch, and whether targeting multiple pathways simultaneously would kill brain tumor cells more effectively than monotherapy.Experimental Design: We used GBM neurosphere lines to investigate the effects of a gamma-secretase inhibitor (MRK-003) on tumor growth, and chromatin immunoprecipitation to study the regulation of other genes by Notch targets. We also evaluated the effect of combined therapy with a Hedgehog inhibitor (cyclopamine) in GBM and medulloblastoma lines, and in primary human GBM cultures.

Hes1: a key role in stemness, metastasis and multidrug resistance

“…For instance, when treated with anti-hedgehog and anti-Notch compounds in vitro, glioma cells show apoptosis phenotype, CSCs depletion and sensitivity to temozolomide. 90,93 As discussed earlier, the third cleavage mediated by g-secretase is a crucial step for Notch activation and is targeted by GSI inhibitors which have been evaluated in phase 1 clinical trials, such as MK-0752, PF-03084014, RO-4929097, reviewed by Takebe N. 94 With the rigorous estimation in preclinical models, it is safe to say that GSI inhibitors do show its anti-proliferation, anti-CSC and pro-apoptotic effects on tumor. However, GSI inhibits Notch target genes without selection which causes a rapid differentiation of intestinal progenitor cells into goblet cells.…”

“…89 Interestingly, Hes1 inhibits Hedgehog signaling by binding to the first intron of Gli1 in brain, prostate, lung, ovarian, skin, and hematopoetic cell cancers. 90 This may suggests a potential chemotherapy resistance mechanism that tumor survives long term Notch-Hes1 inhibition with Gli1 rescuing expression.…”

Notch Signaling in Cell–Cell Communication Pathways

“…Activation of GLI1 has also been shown to induce NOTCH1 and JAGGED1 expression in different regions of the brain [41], whereas HH activates JAG2 expression in motor neuron progenitors [42••]. Conversely, HES1 represses GLI1 expression in glioblastoma cells [43], which may generate a feed-forward regulatory loop. Together, these data reinforce the concept that signaling pathway coordination is required for the proper regulation of cellular decisions in different stem cell systems.…”

Hedgehog signaling in the pathogenesis of neuro-oncology diseases

“…Хотя сигнальный путь HH является первичным механизмом регуляции GLI1, имеются данные о том, что транскрипционный фактор GLI1 может регулироваться другими сигнальными путями [29][30][31][32][33][34][35][36]. Например, было показано стимулирующее влияние белка Ras (семейство малых впервые обнаруженных у крыс с саркомой G-белков) на проникновение GLI1 в ядро [29][30][31].…”

“…не только препятствует транспорту GLI1 в ядро, но и ингибирует активность GLI1 как транскрипционного фактора [2]. Интерактом белков пути HH пересекается с сигнальным путём Notch [36].…”