1. A peptide encoded by upstream open reading frame of MYC binds to tropomyosin receptor kinase B and promotes glioblastoma growth in mice.
- Author
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Li, Fanying, Yang, Kailin, Gao, Xinya, Zhang, Maolei, Gu, Danling, Wu, Xujia, Lu, Chenfei, Wu, Qiulian, Dixit, Deobrat, Gimple, Ryan C., You, Yongping, Mack, Stephen C., Shi, Yu, Kang, Tiebang, Agnihotri, Sameer A., Taylor, Michael D., Rich, Jeremy N., Zhang, Nu, and Wang, Xiuxing
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TUMOR growth ,PEPTIDES ,GLIOBLASTOMA multiforme ,STEM cells ,TROPOMYOSINS ,XENOGRAFTS - Abstract
MYC promotes tumor growth through multiple mechanisms. Here, we show that, in human glioblastomas, the variant MYC transcript encodes a 114–amino acid peptide, MYC pre-mRNA encoded protein (MPEP), from the upstream open reading frame (uORF) MPEP. 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 MYC-associated uORF promotes glioblastoma growth, suggesting a new therapeutic strategy for glioblastoma. Editor's summary: Upstream open reading frames (uORFs) are RNA sequences encoding short peptides that mainly function as translational represssors. Here, Li et al. show that the uORF of the oncogene MYC is translated into a peptide (MPEP) that is secreted from glioblastoma stem cells (GSCs). MPEP expression promoted proliferation of GSCs in vitro and accelerated tumorigenesis in a mouse model. MPEP acted through canonical activation of tropomyosin receptor kinase B, which was corroborated by the increase in survival rates of glioblastoma mice undergoing combination treatment with an MPEP antibody and the TRK inhibitor entrecitinib. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]
- Published
- 2024
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