The protective autophagy activated by GANT-61 in MYCN amplified neuroblastoma cells is mediated by PERK

Area of Science:

• Oncology
• Molecular Biology
• Cellular Biology

Background:

• The proto-oncogene MYC activates the unfolded protein response (UPR), involving PERK (protein kinase R (PKR)-like endoplasmic reticulum kinase).
• PERK regulates autophagy, a process implicated in tumorigenesis, by activating the eIF2α-ATF4 pathway, leading to increased LC3 expression.
• GLI1 and GLI2 repress PERK; their inhibitor, GANT-61, reduces autophagy in MYCN non-amplified neuroblastoma but not in MYCN-amplified cells.

Purpose of the Study:

• To investigate the combined effect of a PERK inhibitor (GSK2606414) and a GLI inhibitor (GANT-61) on neuroblastoma cells with varying MYCN amplification status.
• To determine if targeting the PERK pathway can enhance the efficacy of GLI inhibition in neuroblastoma.

Main Methods:

• Treatment of MYCN-amplified and MYCN non-amplified neuroblastoma cell lines with GSK2606414 and GANT-61, individually and in combination.
• Assessment of autophagy markers, such as LC3, and cell proliferation rates.

Main Results:

• Inhibition of PERK with GSK2606414 impaired GANT-61-induced autophagy specifically in MYCN-amplified neuroblastoma cells.
• The combination therapy showed no significant effect on autophagy in MYCN non-amplified neuroblastoma cells.
• PERK inhibition amplified the efficacy of GANT-61 in reducing proliferation of MYCN-amplified neuroblastoma cells.

Conclusions:

• PERK is a potential therapeutic target for neuroblastoma, particularly in cases with MYCN amplification.
• Combining PERK and GLI inhibition offers a promising strategy to enhance anti-tumor effects in MYCN-amplified neuroblastoma by modulating autophagy.