Protocadherin 17 weakens the lenvatinib resistance of liver cancer through inducing ferroptosis

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research Pub Date : 2025-03-04 DOI:10.1016/j.yexcr.2025.114495

Jun Yang , Bin Hu , Guowei Zhang , Kai Wu , Xue Zhang , Mengxuan Ji , Bin Zhang , Hengliang Shi , Dechun Li

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引用次数: 0

Abstract

Lenvatinib has been employed in the treatment of advanced liver cancer; however, its clinical application is significantly impeded by frequent drug resistance. Recent studies have revealed that lenvatinib treatment triggers ferroptosis in liver cancer cells, providing a novel approach to addressing lenvatinib resistance. In this study, we initially validated the induction of ferroptosis by lenvatinib in liver cancer cells. Remarkably, protocadherin 17 (PCDH17), an adhesion-related protein, was found to be down-regulated in liver cancer, and overexpression of PCDH17 could induce ferroptosis in liver cancer cells. Importantly, silencing PCDH17 inhibited the impact of lenvatinib on liver cancer cell ferroptosis, while overexpression of PCDH17 had the opposite effect. These findings were further confirmed using a xenograft tumor model in BALB/c nude mice. Additionally, lenvatinib-resistant (LR) liver cancer cells were generated for additional validation purposes. It was observed that LR-liver cancer cells lost their susceptibility to ferroptosis induction by lenvatinib; however, overexpression of PCDH17 reactivated their sensitivity to ferroptosis. Corresponding results were also verified in BALB/c nude mice models. In conclusion, these results suggest that as a novel regulator of ferroptosis, PCDH17 can alleviate lenvatinib resistance and potentially enhance the therapeutic efficacy of lenvatinib in treating liver cancer.

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原钙粘蛋白17通过诱导铁下垂削弱肝癌对lenvatinib的耐药性

Lenvatinib已被用于晚期肝癌的治疗；然而，由于耐药频繁，其临床应用受到严重阻碍。最近的研究表明，lenvatinib治疗引发肝癌细胞铁下垂，为解决lenvatinib耐药性提供了一种新的方法。在本研究中，我们初步验证了lenvatinib对肝癌细胞铁下垂的诱导作用。值得注意的是，黏附相关蛋白原钙粘蛋白17 （protocadherin 17, PCDH17）在肝癌中下调，且PCDH17过表达可诱导肝癌细胞铁凋亡。重要的是，沉默PCDH17可以抑制lenvatinib对肝癌细胞铁下垂的影响，而过表达PCDH17则具有相反的作用。这些发现在BALB/c裸鼠异种移植瘤模型中得到进一步证实。此外，为了额外的验证目的，还生成了lenvatinib耐药（LR）肝癌细胞。结果表明，lenvatinib对肝癌细胞失去了铁下垂诱导的敏感性；然而，PCDH17的过表达重新激活了它们对铁下垂的敏感性。在BALB/c裸鼠模型中也验证了相应的结果。综上所述，这些结果提示PCDH17作为铁下垂的新型调节因子，可以减轻lenvatinib耐药性，并可能增强lenvatinib治疗肝癌的疗效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Experimental cell research 医学-细胞生物学

CiteScore

7.20

自引率

0.00%

发文量

295

审稿时长

30 days

期刊介绍： Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.