TRIM25 activates AKT/mTOR by inhibiting PTEN via K63-linked polyubiquitination in non-small cell lung cancer

• 作者: Yuan-ming He Xiu-min Zhou Shuo-yi Jiang Zu-bin Zhang Bi-yin Cao Jin-bao Liu Yuan-ying Zeng Jun Zhao Xin-liang Mao
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2022,（3）
• 所属期刊栏目: Chemotherapy
• 页码范围: 681-691
• 页数: 11页
• 语种: 英文

摘要

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.