Upregulation of protein synthesis and proteasome degradation confers sensitivity to proteasome inhibitor bortezomib in myc-atypical teratoid/rhabdoid tumors

Huy Minh Tran, Kuo Sheng Wu, Shian Ying Sung, Chun Austin Changou, Tsung Han Hsieh, Yun Ru Liu, Yen Lin Liu, Min Lan Tsai, Hsin Lun Lee, Kevin Li Chun Hsieh, Wen Chang Huang, Muh Lii Liang, Hsin Hung Chen, Yi Yen Lee, Shih Chieh Lin, Donald Ming Tak Ho, Feng Chi Chang, Meng En Chao, Wan Chen, Shing Shung ChuAlice L. Yu, Yun Yen, Che Chang Chang, Tai Tong Wong

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number752
JournalCancers
Volume12
Issue number3
DOIs
Publication statusPublished - Mar 22 2020

Keywords

  • Bortezomib
  • Myc-ATRTs
  • P53
  • Proteasome degradation
  • Protein synthesis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Upregulation of protein synthesis and proteasome degradation confers sensitivity to proteasome inhibitor bortezomib in myc-atypical teratoid/rhabdoid tumors'. Together they form a unique fingerprint.

  • Cite this