1. Upregulation of Protein Synthesis and Proteasome Degradation Confers Sensitivity to Proteasome Inhibitor Bortezomib in Myc-Atypical Teratoid/Rhabdoid Tumors
- Author
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Yun Ru Liu, Feng Chi Chang, Muh Lii Liang, Shih-Chieh Lin, Wen Chang Huang, Tsung Han Hsieh, Donald Ming-Tak Ho, Kevin Li Chun Hsieh, Hsin Hung Chen, Meng En Chao, Huy Minh Tran, Yi Yen Lee, Yen Lin Liu, Wan Chen, Chun A. Changou, Che Chang Chang, Min Lan Tsai, Shian Ying Sung, Tai-Tong Wong, Kuo Sheng Wu, Hsin Lun Lee, Alice L. Yu, Yun Yen, and Shing Shung Chu
- Subjects
0301 basic medicine ,p53 ,Cancer Research ,protein synthesis ,Oncology and Carcinogenesis ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Downregulation and upregulation ,Gene expression ,Genetics ,medicine ,2.1 Biological and endogenous factors ,Aetiology ,Multiple myeloma ,Cancer ,Pediatric ,Oncogene ,Chemistry ,Bortezomib ,bortezomib ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,proteasome degradation ,Orphan Drug ,030104 developmental biology ,Oncology ,5.1 Pharmaceuticals ,Apoptosis ,Cell culture ,030220 oncology & carcinogenesis ,Proteasome inhibitor ,Cancer research ,Myc-ATRTs ,Development of treatments and therapeutic interventions ,Biotechnology ,medicine.drug - 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.
- Published
- 2020
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