Liu Fan, Liu Weixiao, Tan Yawen, Shang Yaxin, Ling Sihui, Jiang Xiaokun, Zhang Zhen, Sun Shiyao, Xie Ping
Department of Cell Biology, Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.
Beijing lnstitute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.
Oncogene. 2025 Jun 18. doi: 10.1038/s41388-025-03468-z.
The gradual emergence of a novel therapeutic approach lies in the restoration of tumor suppressive machinery. PTEN is a crucial negative regulator of the PI3K/Akt signaling pathway. Protein neddylation modification contributes to PTEN inactivation and fuels breast cancer progression. Here, we highlight that an elevated level of PTEN neddylation is markedly associated with resistance to palbociclib, a CDK4/6 inhibitor used in luminal subtype breast cancer patients. Mechanistically, PTEN neddylation activates the PI3K/Akt signaling pathway, and more notably, upregulates the activity of the AP-1 transcription factor. Our data showed that PTEN neddylation stabilizes JUND, a transcription factor involved in the AP-1 complex, by disrupting its interaction with the E3 ubiquitin ligase ITCH. Consequently, activated JUND leads to the release of cytokines and chemokines, which in turn may drive an inflammatory tumor microenvironment, potentially contributing to drug resistance. Then, we identified Echinacoside as a potent inhibitor of PTEN neddylation both in vivo and in vitro by disrupting its interaction with XIAP, the E3 ligase responsible for PTEN neddylation. Combination of Echinacoside effectively overcome resistance to palbociclib in breast cancer treatment. These findings highlight targeting PTEN neddylation as a promising strategy for restoring tumor suppressor activity and overcoming resistance.
一种新的治疗方法的逐渐出现在于恢复肿瘤抑制机制。PTEN是PI3K/Akt信号通路的关键负调节因子。蛋白质NEDDylation修饰导致PTEN失活并促进乳腺癌进展。在这里，我们强调PTEN NEDDylation水平升高与对palbociclib（一种用于管腔亚型乳腺癌患者的CDK4/6抑制剂）的耐药性显著相关。机制上，PTEN NEDDylation激活PI3K/Akt信号通路，更值得注意的是，上调AP-1转录因子的活性。我们的数据表明，PTEN NEDDylation通过破坏其与E3泛素连接酶ITCH的相互作用来稳定JUND（一种参与AP-1复合物的转录因子）。因此，激活的JUND导致细胞因子和趋化因子的释放，这反过来可能驱动炎症性肿瘤微环境，潜在地导致耐药性。然后，我们通过破坏紫锥菊苷与负责PTEN NEDDylation的E3连接酶XIAP的相互作用，确定紫锥菊苷在体内和体外都是PTEN NEDDylation的有效抑制剂。紫锥菊苷联合用药有效地克服了乳腺癌治疗中对palbociclib的耐药性。这些发现突出了靶向PTEN NEDDylation作为恢复肿瘤抑制活性和克服耐药性的一种有前景的策略。
