IPO5 contributes to cetuximab resistance in colorectal cancer by modulating Ras signaling.

IF 4.5 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2026-10-05 eCollection Date: 2026-10-16 DOI:10.1016/j.isci.2026.117714

Qinzi Yuan, Siqi Lu, Xiaoxi He, Lin Zheng, Lei Liu, Yujia Chen, Wenjuan Zhang, Xiaomin Li, Yanxia Lu, Xuenong Li

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引用次数: 0

Abstract

Resistance to cetuximab is a major challenge in colorectal cancer (CRC). Here, we show that IPO5, an importin mediating RASAL2 nuclear import, contributes to cetuximab resistance. Screening six CRC cell lines revealed an inverse correlation between IPO5 expression and cetuximab sensitivity, with higher IPO5 levels in resistant (RKO and SW620) than sensitive (LoVo and Caco2) cells. IPO5 knockdown in resistant cells restored cetuximab sensitivity, induced apoptosis (upregulated active caspase-3/BAX and downregulated BCL-2), and suppressed proliferation and xenograft growth, whereas IPO5 overexpression in sensitive cells reduced sensitivity. Mechanistically, IPO5 facilitates RASAL2 nuclear translocation via its nuclear localization signal, depleting cytoplasmic RASAL2 and increasing GTP-bound RAS to sustain AKT and MAPK activation. Consistently, IPO5 and downstream Ras effectors were elevated in resistant LoVo-CR cells. Collectively, our findings identify the IPO5/RASAL2 axis as a key contributor to cetuximab resistance in CRC by disrupting the cytoplasmic localization of RASAL2 and activating the RAS/MAPK and PI3K/AKT pathways.

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IPO5通过调节Ras信号参与结直肠癌西妥昔单抗耐药。

西妥昔单抗耐药是结直肠癌（CRC）的主要挑战。本研究表明，介导RASAL2核输入的输入基因IPO5有助于西妥昔单抗耐药。筛选6个结直肠癌细胞系发现IPO5表达与西妥昔单抗敏感性呈负相关，耐药（RKO和SW620）细胞的IPO5水平高于敏感（LoVo和Caco2）细胞。IPO5在耐药细胞中下调可恢复西妥昔单抗敏感性，诱导凋亡（活性caspase-3/BAX上调，BCL-2下调），抑制增殖和异种移植物生长，而IPO5在敏感细胞中过表达可降低敏感性。机制上，IPO5通过其核定位信号促进RASAL2核易位，耗尽细胞质RASAL2并增加gtp结合的RAS以维持AKT和MAPK的激活。与此一致，IPO5和下游Ras效应物在耐药的LoVo-CR细胞中升高。总的来说，我们的研究结果通过破坏RASAL2的细胞质定位和激活RAS/MAPK和PI3K/AKT通路，确定了IPO5/RASAL2轴是CRC西妥昔单抗耐药的关键因素。

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

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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