Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China.
Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Hunan Normal University, Changsha, Hunan, China.
Cell Death Dis. 2022 May 25;13(5):499. doi: 10.1038/s41419-022-04937-z.
A major reason for the high mortality of patients with bladder cancer (BC) is that chemotherapy and surgery are only effective for very limited patients. Thus, developing novel treatment options becomes an urgent need for improving clinical outcomes and the quality of life for BC patients. Here, we demonstrated that proguanil significantly inhibited the growth of BC in vitro and in vivo. Importantly, our results indicated that the sensitivity of BC cells to proguanil is positively correlated with the expression of epidermal growth factor receptor (EGFR). Mechanistically, proguanil specifically targeted EGFR and promoted EGFR binding to Caveolin-1, enhanced its endocytosis in a Clathrin-independent manner, and then recruited c-Cbl to promote EGFR ubiquitination and degradation through the lysosomal pathway. Further studies suggested that proguanil induced autophagy by destabilizing EGFR and inhibiting its downstream signaling pathway. Thus, this study reveals the novel mechanism of proguanil on anticancer activity and implies the potential benefits of this drug in the treatment of BC.
膀胱癌（BC）患者死亡率高的一个主要原因是化疗和手术仅对非常有限的患者有效。因此，开发新的治疗选择成为改善 BC 患者临床结果和生活质量的迫切需要。在这里，我们证明了咯萘啶显著抑制了 BC 的体外和体内生长。重要的是，我们的结果表明，BC 细胞对咯萘啶的敏感性与表皮生长因子受体（EGFR）的表达呈正相关。在机制上，咯萘啶特异性靶向 EGFR 并促进 EGFR 与 Cav-1 结合，以网格蛋白非依赖性方式增强其内化，然后募集 c-Cbl 通过溶酶体途径促进 EGFR 泛素化和降解。进一步的研究表明，咯萘啶通过破坏 EGFR 及其下游信号通路来诱导自噬。因此，这项研究揭示了咯萘啶在抗癌活性上的新机制，并暗示了该药物在 BC 治疗中的潜在益处。
