Upregulation of Protein Synthesis and Proteasome Degradation Confers Sensitivity to Proteasome Inhibitor Bortezomib in Myc-Atypical Teratoid/Rhabdoid Tumors.
Huy Minh TranKuo-Sheng WuShian-Ying SungChun Austin ChangouTsung-Han HsiehYun-Ru LiuYen-Lin LiuMin-Lan TsaiHsin-Lun LeeKevin Li-Chun HsiehWen-Chang HuangMuh-Lii LiangHsin-Hung ChenYi-Yen LeeShih-Chieh LinDonald Ming-Tak HoFeng-Chi ChangMeng-En ChaoWan ChenShing-Shung ChuAlice Lin-Tsing YuYun YenChe-Chang ChangTai-Tong WongPublished in: Cancers (2020)
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.
Keyphrases
- transcription factor
- gene expression
- multiple myeloma
- signaling pathway
- induced apoptosis
- cell proliferation
- poor prognosis
- endothelial cells
- dna methylation
- oxidative stress
- type diabetes
- stem cells
- bone marrow
- genome wide
- drug delivery
- multiple sclerosis
- skeletal muscle
- cell therapy
- cancer therapy
- metabolic syndrome
- mesenchymal stem cells
- insulin resistance
- combination therapy
- subarachnoid hemorrhage
- smoking cessation
- high fat diet induced
- cerebral ischemia