Oncotarget

Research Papers:

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

Jing Wang _, Siqi Huang, Ruicheng Tian, Jing Chen, Hongxiang Gao, Chenjie Xie, Yuhua Shan, Zhen Zhang, Song Gu and Min Xu

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Oncotarget. 2018; 9:14413-14427. https://doi.org/10.18632/oncotarget.24214

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Abstract

Jing Wang1,*, Siqi Huang1,*, Ruicheng Tian1, Jing Chen1, Hongxiang Gao1, Chenjie Xie1, Yuhua Shan1, Zhen Zhang2,3, Song Gu1 and Min Xu1

1Department of Surgery, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China

2Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China

3Shanghai Pediatric Congenital Heart Disease Institute, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China

*These authors contributed equally to this work

Correspondence to:

Song Gu, email: [email protected]

Min Xu, email: [email protected]

Keywords: neuroblastoma; autophagy; PERK; MYCN-amplified; GANT-61

Received: December 23, 2016     Accepted: November 16, 2017     Epub: January 13, 2018     Published: March 06, 2018

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.


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