Inhibitory role of proguanil on the growth of bladder cancer via enhancing EGFR degradation and inhibiting its downstream signaling pathway to induce autophagy.
Inhibitory role of proguanil on the growth of bladder cancer via enhancing EGFR degradation and inhibiting its downstream signaling pathway to induce autophagy.
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氯胍通过增强EGFR降解并抑制其下游信号通路诱导自噬抑制膀胱癌生长
DOI：
10.1038/s41419-022-04937-z
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发表时间：
2022-05-25
影响因子：
9
通讯作者：
Yang, Xiaoping
中科院分区：
文献类型：
--
作者：
Xiao, Di;Hu, Xin;Peng, Mei;Deng, Jun;Zhou, Sichun;Xu, Simeng;Wu, Jingtao;Yang, Xiaoping
膀胱癌（BC）患者死亡率高的主要原因是化疗和手术仅对非常有限的患者有效。因此，开发新的治疗方案成为改善BC患者临床结局和生活质量的迫切需要。在这里，我们证明了氯胍显着抑制BC在体外和体内的生长。重要的是，我们的结果表明BC细胞对氯胍的敏感性与表皮生长因子受体（EGFR）的表达正相关。从机制上讲，氯胍特异性靶向EGFR并促进EGFR与Caveolin-1结合，以网格蛋白非依赖性方式增强其内吞作用，然后招募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，氯胍诱导自噬通过破坏EGFR的稳定和抑制其下游信号通路。因此，本研究揭示了氯胍抗肿瘤活性的新机制，并暗示了这种药物在治疗BC中的潜在益处。
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.
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影响因子：
15.8
作者：
Chauhan PS;Chen K;Babbra RK;Feng W;Pejovic N;Nallicheri A;Harris PK;Dienstbach K;Atkocius A;Maguire L;Qaium F;Szymanski JJ;Baumann BC;Ding L;Cao D;Reimers MA;Kim EH;Smith ZL;Arora VK;Chaudhuri AA
通讯作者：
Chaudhuri AA
DOI：
10.1073/pnas.0409610102
发表时间：
2005-02-08
影响因子：
11.1
作者：
Friedman, LM;Rinon, A;Yarden, Y
通讯作者：
Yarden, Y
影响因子：
9
作者：
Ma J;Ma S;Zhang Y;Shen Y;Huang L;Lu T;Wang L;Wen Y;Ding Z
通讯作者：
Ding Z
影响因子：
11.5
作者：
Perera, RM;Narita, Y;Johns, TG
通讯作者：
Johns, TG
G 蛋白通路抑制因子 2 通过破坏表皮生长因子受体的稳定性来抑制胃癌。
影响因子：
5.7
作者：
Si Y;Zhang H;Peng P;Zhu C;Shen J;Xiong Y;Liu X;Xiang Y;Li W;Ren Y;Wan F;Zhang L;Liu Y
通讯作者：
Liu Y