Zheng, Si Min and Feng, Yu Chen and Zhu, Qin and Li, Ruo Qi and Yan, Qian Qian and Teng, Liu and Yue, Yi Meng and Han, Man Man and Ye, Kaihong and Zhang, Sheng Nan and Qi, Teng Fei and Tang, Cai Xia and Zhao, Xiao Hong and Zhang, Yuan Yuan and Xu, Liang and Xu, Ran and Xing, Jun and Baker, Mark and Liu, Tao and Thorne, Rick F. and Jin, Lei and Preiss, Thomas and Zhang, Xu Dong and Cang, Shundong and Gao, Jin Nan (2024) MILIP Binding to tRNAs Promotes Protein Synthesis to Drive Triple-Negative Breast Cancer. Cancer Research, 84 (9). pp.1460-1474. ISSN 0008-5472
Full text not available from this repository.Abstract
Patients with triple-negative breast cancer (TNBC) have a poor prognosis due to the lack of effective molecular targets for therapeutic intervention. Here we found that the long noncoding RNA (lncRNA) MILIP supports TNBC cell survival, proliferation, and tumorigenicity by complexing with transfer RNAs (tRNA) to promote protein production, thus representing a potential therapeutic target in TNBC. MILIP was expressed at high levels in TNBC cells that commonly harbor loss-of-function mutations of the tumor suppressor p53, and MILIP silencing suppressed TNBC cell viability and xenograft growth, indicating that MILIP functions distinctively in TNBC beyond its established role in repressing p53 in other types of cancers. Mechanistic investigations revealed that MILIP interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1alpha1) and formed an RNA-RNA duplex with the type II tRNAs tRNALeu and tRNASer through their variable loops, which facilitated the binding of eEF1alpha1 to these tRNAs. Disrupting the interaction between MILIP and eEF1alpha1 or tRNAs diminished protein synthesis and cell viability. Targeting MILIP inhibited TNBC growth and cooperated with the clinically available protein synthesis inhibitor omacetaxine mepesuccinate in vivo. Collectively, these results identify MILIP as an RNA translation elongation factor that promotes protein production in TNBC cells and reveal the therapeutic potential of targeting MILIP, alone and in combination with other types of protein synthesis inhibitors, for TNBC treatment. SIGNIFICANCE: LncRNA MILIP plays a key role in supporting protein production in TNBC by forming complexes with tRNAs and eEF1alpha1, which confers sensitivity to combined MILIP targeting and protein synthesis inhibitors.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 25 Dec 2024 23:17 |
| Last Modified: | 25 Dec 2024 23:17 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/1577 |
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