A peptide encoded by upstream open reading frame of MYC binds to tropomyosin receptor kinase B and promotes glioblastoma growth in mice

Fanying Li; Kailin Yang; Xinya Gao; Maolei Zhang; Danling Gu; Xujia Wu; Chenfei Lu; Qiulian Wu; Deobrat Dixit; Ryan C Gimple; Yongping You; Stephen C Mack; Yu Shi; Tiebang Kang; Sameer A Agnihotri; Michael D Taylor; Jeremy N Rich; Nu Zhang; Xiuxing Wang

doi:10.1126/scitranslmed.adk9524

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A peptide encoded by upstream open reading frame of MYC binds to tropomyosin receptor kinase B and promotes glioblastoma growth in mice

Journal article

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A peptide encoded by upstream open reading frame of MYC binds to tropomyosin receptor kinase B and promotes glioblastoma growth in mice

Fanying Li, Kailin Yang, Xinya Gao, Maolei Zhang, Danling Gu, Xujia Wu, Chenfei Lu, Qiulian Wu, Deobrat Dixit, Ryan C Gimple, …

Science translational medicine, Vol.16(767), eadk9524

10/02/2024

DOI: 10.1126/scitranslmed.adk9524

PMID: 39356747

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Abstract

MYC promotes tumor growth through multiple mechanisms. Here, we show that, in human glioblastomas, the variant transcript encodes a 114-amino acid peptide, MYC pre-mRNA encoded protein (MPEP), from the upstream open reading frame (uORF) . Secreted MPEP promotes patient-derived xenograft tumor growth in vivo, independent of MYC through direct binding, and activation of tropomyosin receptor kinase B (TRKB), which induces downstream AKT-mTOR signaling. Targeting MPEP through genetic ablation reduced growth of patient-derived 4121 and 3691 glioblastoma stem cells. Administration of an MPEP-neutralizing antibody in combination with a small-molecule TRKB inhibitor reduced glioblastoma growth in patient-derived xenograft tumor-bearing mice. The overexpression of MPEP in surgical glioblastoma specimens predicted a poor prognosis, supporting its clinical relevance. In summary, our results demonstrate that tumor-specific translation of a -associated uORF promotes glioblastoma growth, suggesting a new therapeutic strategy for glioblastoma.

Signal Transduction

Animals

Cell Line, Tumor

Cell Proliferation - drug effects

Gene Expression Regulation, Neoplastic

Glioblastoma - drug therapy

Glioblastoma - genetics

Glioblastoma - metabolism

Glioblastoma - pathology

Humans

Mice

Open Reading Frames - genetics

Peptides - metabolism

Protein Binding

Proto-Oncogene Proteins c-akt - metabolism

Proto-Oncogene Proteins c-myc - metabolism

Receptor, trkB - metabolism

TOR Serine-Threonine Kinases - metabolism

Details

Title: Subtitle: A peptide encoded by upstream open reading frame of MYC binds to tropomyosin receptor kinase B and promotes glioblastoma growth in mice
Creators: Fanying Li - The First Affiliated Hospital, Sun Yat-sen University
Kailin Yang - Cleveland Clinic
Xinya Gao - The First Affiliated Hospital, Sun Yat-sen University
Maolei Zhang - The First Affiliated Hospital, Sun Yat-sen University
Danling Gu - Nanjing Medical University
Xujia Wu - University of Pittsburgh Medical Center
Chenfei Lu - Nanjing Medical University
Qiulian Wu - University of Pittsburgh Medical Center
Deobrat Dixit - University of California, San Diego
Ryan C Gimple - Washington University in St. Louis
Yongping You - Nanjing Medical University
Stephen C Mack - St. Jude Children's Research Hospital
Yu Shi - Southwest Hospital
Tiebang Kang - Sun Yat-sen University Cancer Center
Sameer A Agnihotri - University of Pittsburgh Medical Center
Michael D Taylor - Hospital for Sick Children
Jeremy N Rich - University of Pittsburgh Medical Center
Nu Zhang - The First Affiliated Hospital, Sun Yat-sen University
Xiuxing Wang - Nanjing Medical University
Resource Type: Journal article
Publication Details: Science translational medicine, Vol.16(767), eadk9524
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.adk9524
PMID: 39356747
ISSN: 1946-6234
eISSN: 1946-6242
Grant note: National Natural Science Outstanding Youth Foundation of China: 81822033 Major Program of the National Natural Science Foundation China: 82192894 The special Funds of the National Natural Science Foundation of China: 82341007 National Natural Science Foundation of China: 82072779, 82302924, 82203525 American Cancer Society Lisa Dean Mosley Cancer Stem Cell Consortium: CSCC-LEAD-22-186-01-CSCC NIH: R01CA268634, R01NS103434, R01CA238662, R35CA197718 Computational Genomic Epidemiology of Cancer (CoGEC) Program at Case Comprehensive Cancer Center: T32CA094186
This work was supported by the National Natural Science Outstanding Youth Foundation of China (81822033 to N.Z.),the Major Program of the National Natural Science Foundation China (82192894 to N.Z.), the special Funds of the National Natural Science Foundation of China (82341007 to N.Z.), the National Natural Science Foundation of China (82072779 to Wang, 82302924 to F.L., and 82203525 to X.G.), the American Cancer Society Lisa Dean Mosley Cancer Stem Cell Consortium (CSCC-LEAD-22-186-01-CSCC to J.N.R.), and the NIH grants (R01CA268634, R01NS103434, R01CA238662, and R35CA197718 to J.N.R.). K.Y. was supported by the Computational Genomic Epidemiology of Cancer (CoGEC) Program at Case Comprehensive Cancer Center (T32CA094186), a Young Investigator Award in Glioblastoma from ASCO Conquer Cancer Foundation, and an RSNA Research Fellow Grant.
Language: English
Date published: 10/02/2024
Academic Unit: Radiation Oncology
Record Identifier: 9984722564102771

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