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细胞质中的p21通过抑制促凋亡蛋白Chk2介导5-氟尿嘧啶耐药性。

Cytoplasmic p21 Mediates 5-Fluorouracil Resistance by Inhibiting Pro-Apoptotic Chk2.

作者信息

Maiuthed Arnatchai, Ninsontia Chuanpit, Erlenbach-Wuensch Katharina, Ndreshkjana Benardina, Muenzner Julienne K, Caliskan Aylin, Husayn Ahmed P, Chaotham Chatchai, Hartmann Arndt, Vial Roehe Adriana, Mahadevan Vijayalakshmi, Chanvorachote Pithi, Schneider-Stock Regine

机构信息

Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.

Experimental Tumor Pathology, University Hospital of Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.

出版信息

Cancers (Basel). 2018 Oct 9;10(10):373. doi: 10.3390/cancers10100373.

DOI:10.3390/cancers10100373
PMID:30304835
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6210175/
Abstract

The oncogenic cytoplasmic p21 contributes to cancer aggressiveness and chemotherapeutic failure. However, the molecular mechanisms remain obscure. Here, we show for the first time that cytoplasmic p21 mediates 5-Fluorouracil (5FU) resistance by shuttling p-Chk2 out of the nucleus to protect the tumor cells from its pro-apoptotic functions. We observed that cytoplasmic p21 levels were up-regulated in 5FU-resistant colorectal cancer cells in vitro and the in vivo Chorioallantoic membrane (CAM) model. Kinase array analysis revealed that p-Chk2 is a key target of cytoplasmic p21. Importantly, cytoplasmic form of p21 mediated by p21 transfection diminished p-Chk2-mediated activation of E2F1 and apoptosis induction. Co-immunoprecipitation, immunofluorescence, and proximity ligation assay showed that p21 forms a complex with p-Chk2 under 5FU exposure. Using in silico computer modeling, we suggest that the p21/p-Chk2 interaction hindered the nuclear localization signal of p-Chk2, and therefore, the complex is exported out of the nucleus. These findings unravel a novel mechanism regarding an oncogenic role of p21 in regulation of resistance to 5FU-based chemotherapy. We suggest a possible value of cytoplasmic p21 as a prognosis marker and a therapeutic target in colorectal cancer patients.

摘要

致癌性细胞质p21会促进癌症侵袭性和化疗失败。然而，其分子机制仍不清楚。在此，我们首次表明，细胞质p21通过将p-Chk2转运出细胞核以保护肿瘤细胞免受其促凋亡功能的影响，从而介导对5-氟尿嘧啶（5FU）的耐药性。我们观察到，在体外5FU耐药的结肠癌细胞和体内尿囊膜（CAM）模型中，细胞质p21水平上调。激酶阵列分析显示，p-Chk2是细胞质p21的关键靶点。重要的是，p21转染介导的细胞质形式的p21减少了p-Chk2介导的E2F1激活和凋亡诱导。免疫共沉淀、免疫荧光和邻近连接分析表明，在5FU暴露下，p21与p-Chk2形成复合物。使用计算机模拟，我们认为p21/p-Chk2相互作用阻碍了p-Chk2的核定位信号，因此，该复合物被转运出细胞核。这些发现揭示了p21在调节对基于5FU的化疗耐药性中的致癌作用的新机制。我们认为细胞质p21作为结肠癌患者的预后标志物和治疗靶点可能具有价值。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c1/6210175/b44fd76f11c5/cancers-10-00373-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c1/6210175/f1e89a2a719e/cancers-10-00373-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c1/6210175/437becef4289/cancers-10-00373-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c1/6210175/e2e05302e19c/cancers-10-00373-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c1/6210175/5d03a0d5353f/cancers-10-00373-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c1/6210175/f44ad046ad52/cancers-10-00373-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c1/6210175/379ea354b3eb/cancers-10-00373-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c1/6210175/b44fd76f11c5/cancers-10-00373-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c1/6210175/f1e89a2a719e/cancers-10-00373-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c1/6210175/437becef4289/cancers-10-00373-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c1/6210175/e2e05302e19c/cancers-10-00373-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c1/6210175/5d03a0d5353f/cancers-10-00373-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c1/6210175/f44ad046ad52/cancers-10-00373-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c1/6210175/379ea354b3eb/cancers-10-00373-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c1/6210175/b44fd76f11c5/cancers-10-00373-g008.jpg

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