VASH2 enhances KIF3C-mediated EGFR-endosomal recycling to promote aggression and chemoresistance of lung squamous cell carcinoma by increasing tubulin detyrosination.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY Cell Death & Disease Pub Date : 2024-10-23 DOI:10.1038/s41419-024-07155-x
Jing Wang, Pengpeng Liu, Rui Zhang, Biyuan Xing, Guidong Chen, Lei Han, Jinpu Yu
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Abstract

Lung squamous cell carcinoma (LUSC) is associated with high mortality and has few therapeutic options. Chemotherapy remains the main treatment for LUSC patients, but multi-drug resistance has become the dominant challenge in the failure of chemotherapy in various cancers. Therefore, the effective therapeutic strategy for LUSC patients is an urgent unmet need. Here, we found vasohibin-2 (VASH2) was a prognostic biomarker for LUSC patients, and VASH2 promoted the malignant biological behaviors of LUSC cells and chemoresistance by increasing the detyrosination of α-tubulin. The high level of detyrosinated-tubulin was negatively associated with patient prognosis. Blocking the tubulin carboxypeptidase (TCP) activity of VASH2 inhibited the xenograft tumor growth and improved the treatment efficacy of paclitaxel in vivo. Results revealed that VASH2-induced increase in tubulin detyrosination boosted the binding of kinesin family member 3C (KIF3C) to microtubules and enhanced KIF3C-dependent endosomal recycling of EGFR, leading to the prolonged activation of PI3K/Akt/mTOR signaling. This study demonstrated that VASH2 was not only a prognostic biomarker but also a promising therapeutic target in LUSC, which offers a novel insight that combination of chemotherapy and EpoY, a TCP inhibitor, may be a promising treatment strategy for LUSC patients.

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VASH2 通过增加微管蛋白的脱酪氨酸化,增强 KIF3C 介导的表皮生长因子受体-内体循环,从而促进肺鳞癌的侵袭性和化疗耐药性。
肺鳞状细胞癌(LUSC)死亡率高,治疗方法少。化疗仍是肺鳞癌患者的主要治疗手段,但多种药物耐药性已成为各种癌症化疗失败的主要挑战。因此,针对 LUSC 患者的有效治疗策略是一个亟待解决的问题。我们发现血管抑制素-2(VASH2)是LUSC患者的预后生物标志物,VASH2通过增加α-微管蛋白的脱酪氨酸化促进了LUSC细胞的恶性生物学行为和化疗耐药性。高水平的脱酪氨酸化微管蛋白与患者的预后呈负相关。阻断VASH2的微管蛋白羧肽酶(TCP)活性可抑制异种移植肿瘤的生长,并提高紫杉醇在体内的治疗效果。研究结果表明,VASH2诱导的小管蛋白脱酪氨酸化的增加促进了驱动蛋白家族成员3C(KIF3C)与微管的结合,并增强了KIF3C依赖的表皮生长因子受体(EGFR)的内体再循环,从而导致PI3K/Akt/mTOR信号的延长激活。这项研究表明,VASH2不仅是LUSC的预后生物标志物,也是一个很有前景的治疗靶点,这为化疗与TCP抑制剂EpoY联合治疗LUSC患者提供了新的思路。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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