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Upregulation of Protein Synthesis and Proteasome Degradation Confers Sensitivity to Proteasome Inhibitor Bortezomib in Myc-Atypical Teratoid/Rhabdoid Tumors
- Source :
- Cancers, Volume 12, Issue 3, Cancers, vol 12, iss 3, Cancers, Vol 12, Iss 3, p 752 (2020)
- Publication Year :
- 2020
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2020.
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 20726694
- Database :
- OpenAIRE
- Journal :
- Cancers
- Accession number :
- edsair.doi.dedup.....e8996082f141ec93820b59a203e75680
- Full Text :
- https://doi.org/10.3390/cancers12030752