RCC1 regulation of subcellular protein localization via Ran GTPase drives pancreatic ductal adenocarcinoma growth

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2024-09-24 DOI:10.1016/j.canlet.2024.217275

Sahar F. Bannoura , Amro Aboukameel , Husain Yar Khan , Md Hafiz Uddin , Hyejeong Jang , Eliza W Beal , Amalraj Thangasamy , Yang Shi , Seongho Kim , Kay-Uwe Wagner , Rafic Beydoun , Bassel F. El-Rayes , Philip A. Philip , Ramzi M. Mohammad , Muhammad Wasif Saif , Mohammed Najeeb Al-Hallak , Boris C. Pasche , Asfar S. Azmi

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引用次数: 0

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with limited therapeutic options. Here, we evaluated the role of regulator of chromosome condensation 1 (RCC1) in PDAC. RCC1 functions as a guanine exchange factor for GTP-binding nuclear protein Ran (Ran) GTPase and is involved in nucleocytoplasmic transport. RCC1 RNA expression is elevated in PDAC tissues compared to normal pancreatic tissues and correlates with poor prognosis. RCC1 silencing by RNAi and CRISPR-Cas9 knockout (KO) results in reduced proliferation in 2-D and 3-D cell cultures. RCC1 knockdown (KD) reduced migration and clonogenicity, enhanced apoptosis, and altered cell cycle progression in human PDAC and murine cells from LSL-Kras^G12D/+; LSL-Trp53^R172H/+; Pdx1-Cre (KPC) tumors. Mechanistically, RCC1 KO shows widespread transcriptomic alterations including regulation of PTK7, a co-receptor of the Wnt signaling pathway. RCC1 KD disrupted subcellular Ran localization and the Ran gradient. Nuclear and cytosolic proteomics revealed altered subcellular proteome localization in Rcc1 KD KPC-tumor-derived cells and several altered metabolic biosynthesis pathways. In vivo, RCC1 KO cells show reduced tumor growth potential when injected as sub-cutaneous xenografts. Finally, RCC1 KD sensitized PDAC cells to gemcitabine chemotherapy treatment. This study reveals the role of RCC1 in pancreatic cancer as a novel molecular vulnerability that could be exploited to enhance therapeutic response.

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RCC1 通过 Ran GTPase 对亚细胞蛋白定位的调控驱动胰腺导管腺癌生长

胰腺导管腺癌（PDAC）是一种致死率极高的恶性肿瘤，但治疗方案有限。在此，我们评估了染色体凝聚调节因子 1（RCC1）在 PDAC 中的作用。RCC1 是 GTP 结合核蛋白 Ran（Ran）GTPase 的鸟嘌呤交换因子，参与核胞质转运。与正常胰腺组织相比，RCC1 RNA 在 PDAC 组织中的表达较高，并且与不良预后相关。通过 RNAi 和 CRISPR-Cas9 敲除（KO）沉默 RCC1 会导致二维和三维细胞培养物的增殖减少。在人类 PDAC 和来自 LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) 肿瘤的小鼠细胞中，RCC1 基因敲除（KD）减少了迁移和克隆生成，增强了细胞凋亡，并改变了细胞周期的进展。从机理上讲，RCC1 KO 显示出广泛的转录组改变，包括对 PTK7（Wnt 信号通路的共受体）的调控。RCC1 KD破坏了亚细胞Ran定位和Ran梯度。核蛋白质组学和细胞膜蛋白质组学显示，Rcc1 KD KPC-肿瘤衍生细胞中的亚细胞蛋白质组定位发生了改变，几种代谢生物合成途径也发生了改变。在体内，RCC1 KO 细胞作为皮下异种移植注射后，肿瘤生长潜力降低。最后，RCC1 KD 使 PDAC 细胞对吉西他滨化疗敏感。这项研究揭示了 RCC1 在胰腺癌中的作用，它是一种新的分子脆弱性，可用于增强治疗反应。

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

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.