蛋白質合成和蛋白酶體降解作用之正調控賦予非典型橫紋肌樣瘤對蛋白酶體抑製劑萬科(Bortezomib)之敏應性

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

Tran Minh Huy(Tran Minh Huy)

指導教授 ： 黃棣棟

臺北醫學大學/醫學院/國際醫學研究博士學位學程/博士(2020年)

摘要

Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Non-specific and traditional cytotoxicity treatments offer low disease control rates and cause some long-term neurocognitive sequelae in young children, highlighting the urgency of targeted therapies. The primary genetic aberration in ATRTs is the loss of SMARCB1 or very rarely SMARCA4 genes. One consequence of the SMARCB1 depletion is the upregulation of MYC signaling pathway. ATRTs comprise of three distinct molecular subgroups, including ATRT-SHH, ATRT-TYR, and ATRT-MYC. ATRT-MYC is driven by the MYC oncogene, which directly controls the intracellular protein synthesis rate. The Food and Drug Administration approved proteasome inhibitor bortezomib (BTZ) as a primary treatment for multiple myeloma. This study aimed at determining whether the upregulation of protein synthesis and proteasome degradation in ATRTs, particularly in the MYC subgroup, 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. The expressions of proteasome-encoding genes were compared among this paired model as well as between the 24 human ATRT samples and normal brain tissues. The antitumor effect of BTZ was evaluated in three human ATRT-MYC cell lines (PDX-derived tumor cell line Re1-P6, BT-12, and CHLA-266), two human ATRT-SHH cell lines (CHLA-02 and CHLA-04), and in the orthotopic xenograft models of Re1-P6 cell.
Concomitant upregulation of the Myc pathway, protein synthesis, and proteasome degradation were identified in recurrent ATRTs. Additionally, we found that 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 ATRT-MYC cell lines. Additionally, ATRT-SHH cell lines were also sensitive to a clinically achievable concentration of BTZ, but less sensitive than ATRT-MYC. Furthermore, BTZ inhibited tumor growth and prolonged the survival of ATRT-MYC orthotopic xenograft mice.
Our findings suggest that BTZ may be a promising targeted therapy for ATRTs, particularly ATRT-MYC. Together, these preclinical data provided a substantial background for conducting future clinical trials of BTZ in ATRTs.

關鍵字

非典型橫紋肌-MYC ； 蛋白質合成 ； 蛋白酶蛋白酶體抑製劑萬科(Bortezomib)

並列摘要

Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Non-specific and traditional cytotoxicity treatments offer low disease control rates and cause some long-term neurocognitive sequelae in young children, highlighting the urgency of targeted therapies. The primary genetic aberration in ATRTs is the loss of SMARCB1 or very rarely SMARCA4 genes. One consequence of the SMARCB1 depletion is the upregulation of MYC signaling pathway. ATRTs comprise of three distinct molecular subgroups, including ATRT-SHH, ATRT-TYR, and ATRT-MYC. ATRT-MYC is driven by the MYC oncogene, which directly controls the intracellular protein synthesis rate. The Food and Drug Administration approved proteasome inhibitor bortezomib (BTZ) as a primary treatment for multiple myeloma. This study aimed at determining whether the upregulation of protein synthesis and proteasome degradation in ATRTs, particularly in the MYC subgroup, 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. The expressions of proteasome-encoding genes were compared among this paired model as well as between the 24 human ATRT samples and normal brain tissues. The antitumor effect of BTZ was evaluated in three human ATRT-MYC cell lines (PDX-derived tumor cell line Re1-P6, BT-12, and CHLA-266), two human ATRT-SHH cell lines (CHLA-02 and CHLA-04), and in the orthotopic xenograft models of Re1-P6 cell.
Concomitant upregulation of the Myc pathway, protein synthesis, and proteasome degradation were identified in recurrent ATRTs. Additionally, we found that 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 ATRT-MYC cell lines. Additionally, ATRT-SHH cell lines were also sensitive to a clinically achievable concentration of BTZ, but less sensitive than ATRT-MYC. Furthermore, BTZ inhibited tumor growth and prolonged the survival of ATRT-MYC orthotopic xenograft mice.
Our findings suggest that BTZ may be a promising targeted therapy for ATRTs, particularly ATRT-MYC. Together, these preclinical data provided a substantial background for conducting future clinical trials of BTZ in ATRTs.

並列關鍵字

ATRT-MYC ； protein synthesis ； proteasome degradation ； bortezomib ； p53

參考文獻

1. Shih RY, Koeller KK: Embryonal Tumors of the Central Nervous System: From the Radiologic Pathology Archives. RadioGraphics 2018, 38(2):525-541.

2. Scheithauer BW: Development of the WHO classification of tumors of the central nervous system: a historical perspective. Brain Pathol 2009, 19(4):551-564.

3. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007, 114(2):97-109.

4. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW: The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016, 131(6):803-820.

5. Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, Barnholtz-Sloan JS: CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012-2016. Neuro-oncology 2019, 21(Supplement_5):v1-v100.