Disruption of the EGFR-SQSTM1 interaction by a stapled peptide suppresses lung cancer via activating autophagy and inhibiting EGFR signaling
Disruption of the EGFR-SQSTM1 interaction by a stapled peptide suppresses lung cancer via activating autophagy and inhibiting EGFR signaling
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钉合肽破坏 EGFR-SQSTM1 相互作用，通过激活自噬和抑制 EGFR 信号传导抑制肺癌
DOI：
10.1016/j.canlet.2020.01.004
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发表时间：
2020-01-01
期刊：
影响因子：
9.7
通讯作者：
Hua, Fang
中科院分区：
文献类型：
--
作者：
Yu, Jiao-jiao;Zhou, Dan-dan;Hua, Fang
尽管表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）在治疗携带EGFR激活突变的非小细胞肺癌（NSCLC）方面取得了成功，但内在或获得性耐药仍然是疾病长期缓解的主要障碍。缺陷性自噬已被报道为EGFR-TKI抗性机制。然而，EGFR如何调节自噬通量仍不完全清楚。我们发现，EGFR刺激的SQSTM 1酪氨酸433位磷酸化诱导其乌巴结构域的二聚化，从而干扰SQSTM 1的螯合功能并导致自噬通量阻断。SAH-EJ 2是一种优化EGFR衍生肽，与原型相比，无论EGFR突变状态如何，其对NSCLC的体外和体内抗肿瘤活性均增强。从机制上讲，SAH-EJ 2破坏EGFR-SQSTM 1相互作用，并防止EGFR诱导的SQSTM 1磷酸化，这阻碍了SQSTM 1乌巴结构域的二聚化并恢复SQSTM 1货物功能。此外，SAH-EJ 2通过阻断其二聚化和降低其蛋白质稳定性来抑制EGFR活性，这会重新激活核心自噬机制。我们的观察结果表明，通过SAH-EJ 2干扰EGFR-SQSTM 1相互作用，通过同时抑制EGFR信号传导和激活自噬，为NSCLC的治疗提供了一种潜在的策略。
Despite the success of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations, intrinsic or acquired resistance remains the major obstacle to long-term disease remission. Defective autophagy has been reported as an EGFR-TKI resistance mechanism. However, how EGFR regulate autophagic flux are still not fully understood. Here we found that EGFR-stimulated phosphorylation of SQSTM1 at tyrosine 433 induces dimerization of its UBA domain, which disturbs the sequestration function of SQSTM1 and causes autophagic flux blocking. SAH-EJ2, a staple optimized EGFR-derived peptide, showed enhanced in vitro and in vivo antitumor activity against NSCLC than the prototype regardless of EGFR mutation status. Mechanistically, SAH-EJ2 disrupts the EGFR-SQSTM1 interaction and protects against EGFR-induced SQSTM1 phosphorylation, which hinders the dimerization of the SQSTM1 UBA domains and restores SQSTM1 cargo function. Moreover, SAH-EJ2 suppresses EGFR activity by blocking its dimerization and reducing its protein stability, which reciprocally activates the core autophagy machinery. Our observations reveal that disturbing the EGFR-SQSTM1 interaction by SAH-EJ2 confers a potential strategy in the treatment of NSCLC through suppressing EGFR signalling and activating autophagy simultaneously.