Abstract
The PTEN/AKT/mTOR signaling pathway is frequently dysregulated in non-small cell lung cancer (NSCLC), but the mechanisms are not well-understood. The present study found that the ubiquitin ligase TRIM25 is highly expressed in NSCLC tissues and promotes NSCLC cell survival and tumor growth. Mechanistic studies revealed that TRIM25 binds to PTEN and mediates its K63-linked ubiquitination at K266. This modification prevents the plasma membrane translocation of PTEN and reduces its phosphatase activity therefore accumulating PI(3,4,5)P3. TRIM25 thus activates the AKT/mTOR signaling. Moreover, we found that the antibacterial nitroxoline can activate PTEN by reducing its K63-linked polyubiquitination and sensitizes NSCLC to cisplatin-induced apoptosis. This study thus identified a novel modulation on the PTEN signaling pathway by TRIM25 and provides a potential target for NSCLC treatment.
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Acknowledgements
This work was partly supported by the National Natural Science Foundation of China (#81672934 to JZ, #81770154 to XLM) by Suzhou Municipal Science and Technology Project for People’s Livelihood (#SYS201902 to YYZ). The authors thanked to all the patients who donated NSCLC tissues for the study. The authors also thanked to the Nanshan Scholar Project of Guangzhou Medical University.
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Conception and design: XLM, JZ, and YYZ. Development of methods: XLM, YMH, XMZ, SYJ, ZBZ, and BYC. Acquisition of data: XLM, XMZ, YMH. Analysis and interpretation of data: XLM, YYZ, YMH, and JBL. Writing and composition: XLM and YMH. Administration, technical, and material support: XLM and YYZ.
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He, Ym., Zhou, Xm., Jiang, Sy. et al. TRIM25 activates AKT/mTOR by inhibiting PTEN via K63-linked polyubiquitination in non-small cell lung cancer. Acta Pharmacol Sin 43, 681–691 (2022). https://doi.org/10.1038/s41401-021-00662-z
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DOI: https://doi.org/10.1038/s41401-021-00662-z
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