Abstract
The proto-oncogene MYC can trigger the unfolded protein response (UPR). The double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK), one of three primary branches of the UPR, is a key regulator of autophagy, promoting tumorigenesis. Upon activation of PERK, there is an increase in phosphorylation of the eukaryotic initiation factor-2 alpha (eIF2α), which in turn, activates the transcription factor-4 (ATF4), responsible for an increased expression of LC3, a common autophagy marker. PERK is repressed upon GLI1 and GLI2 induction. GANT-61 is an inhibitor of GLI1 and GLI2, known to reduce autophagy in MYCN non-amplified, but not in MYCN amplified neuroblastoma (NB) cells. In our study, we tested the effect of the joint administration of a PERK inhibitor (GSK2606414) and the GLI inhibitor GANT-61 to MYCN amplified and MYCN non-amplified NB cells. Our results suggest that inhibition of PERK impairs GANT-61 induced autophagy in NB cells with MYCN amplification, but had no effect on the MYCN non-amplified NB cells. In summary, PERK seems to be a good therapeutic target for NB. Inhibition of PERK reduces autophagy in MYCN amplified NB cells, thus amplifying the efficacy of the GLI inhibitor GANT-61 in reducing proliferation of this type of cancer cells.
Highlights
Neuroblastoma (NB) is the most common extracranial solid tumor in early childhood with an estimated incidence of 1 per 8,000 to 10,000 births [1, 2]
As previous studies reported that protein kinase-like endoplasmic reticulum kinase (PERK) is repressed upon Gli1 and Gli2 induction [28] and that GANT-61 is an inhibitor of Gli1 and Gli2, we hypothesized that GANT-61 activates PERK through the induction of the PERK-eIF2αATF4 pathway
Our previous findings confirmed that Hh signaling Gli1, Gli2 inhibitor GANT-61 induced apoptosis and induced autophagy in NB cells
Summary
Neuroblastoma (NB) is the most common extracranial solid tumor in early childhood with an estimated incidence of 1 per 8,000 to 10,000 births [1, 2]. The aberrant activation of signaling pathways is common during tumor development. The hedgehog (Hh) signaling pathway is important during early embryogenesis where it promotes cell growth and differentiation, tissue patterning, and vascularization [6, 7]. Aberrant activation of components of the Hh signaling pathway may promote the differentiation of several tumors and have been linked to cancer-related hallmark processes. Due to its important role in tumorgenesis, anticancer drugs based on Hh ligand antagonists (e.g., 5E1 and robotnikinin), Smo inhibitors (e.g., GDC-0449 and IPI926), and GLI transcriptional activity inhibitors (e.g., GANT-58 and GANT-61) have been developed [12,13,14]
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