Affordable Access

Access to the full text

Upregulation of Protein Synthesis and Proteasome Degradation Confers Sensitivity to Proteasome Inhibitor Bortezomib in Myc-Atypical Teratoid/Rhabdoid Tumors

Authors
  • Tran, Huy Minh1
  • Wu, Kuo-Sheng2
  • Sung, Shian-Ying3
  • Changou, Chun Austin3,
  • Hsieh, Tsung-Han4
  • Liu, Yun-Ru4
  • Liu, Yen-Lin5, 6, 7
  • Tsai, Min-Lan5, 6, 7
  • Lee, Hsin-Lun8
  • Hsieh, Kevin Li-Chun
  • Huang, Wen-Chang
  • Liang, Muh-Lii9
  • Chen, Hsin-Hung9
  • Lee, Yi-Yen9
  • Lin, Shih-Chieh10
  • Ho, Donald Ming-Tak10, 11
  • Chang, Feng-Chi
  • Chao, Meng-En2
  • Chen, Wan2
  • Chu, Shing-Shung2
  • And 4 more
  • 1 Department of Neurosurgery, Faculty of Medicine, University of Medicine and Pharmacy at Ho Chi Minh City 700000, Vietnam
  • 2 (S.-S.C.)
  • 3 (C.A.C.)
  • 4 (Y.-R.L.)
  • 5 (M.-L.T.)
  • 6 Department of Pediatrics, Taipei Medical University Hospital, Taipei 110, Taiwan
  • 7 Pediatric Brain Tumor Program, Taipei Cancer Center, Taipei Medical University, Taipei 110, Taiwan
  • 8 Taipei Cancer Center, Taipei Medical University, Taipei 110, Taiwan
  • 9 (Y.-Y.L.)
  • 10 (D.M.-T.H.)
  • 11 Department of Pathology and Laboratory Medicine, Cheng Hsin General Hospital, Taipei 112, Taiwan
  • 12 Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
  • 13 TMU Research Center of Cancer Translational Medicine, Taipei Medical University Taipei, Taipei 110, Taiwan
  • 14 Neuroscience Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan
  • 15 Division of Pediatric Neurosurgery, Department of Neurosurgery, Taipei Medical University Hospital and Taipei Neuroscience Institute, Taipei Medical University, Taipei 110, Taiwan
Type
Published Article
Journal
Cancers
Publisher
MDPI AG
Publication Date
Mar 22, 2020
Volume
12
Issue
3
Identifiers
DOI: 10.3390/cancers12030752
PMID: 32235770
PMCID: PMC7140067
Source
PubMed Central
Keywords
License
Green

Abstract

Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Myc-ATRT is driven by the Myc oncogene, which directly controls the intracellular protein synthesis rate. Proteasome inhibitor bortezomib (BTZ) was approved by the Food and Drug Administration as a primary treatment for multiple myeloma. This study aimed to determine whether the upregulation of protein synthesis and proteasome degradation in Myc-ATRTs increases tumor cell sensitivity to BTZ. We performed differential gene expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT. Concomitant upregulation of the Myc pathway, protein synthesis and proteasome degradation were identified in recurrent ATRTs. Additionally, we found the proteasome-encoding genes were highly expressed in ATRTs compared with in normal brain tissues, correlated with the malignancy of tumor cells and were essential for tumor cell survival. BTZ inhibited proliferation and induced apoptosis through the accumulation of p53 in three human Myc-ATRT cell lines (PDX-derived tumor cell line Re1-P6, BT-12 and CHLA-266). Furthermore, BTZ inhibited tumor growth and prolonged survival in Myc-ATRT orthotopic xenograft mice. Our findings suggest that BTZ may be a promising targeted therapy for Myc-ATRTs.

Report this publication

Statistics

Seen <100 times