CD73, a Promising Therapeutic Target of Diclofenac, Promotes Metastasis of Pancreatic Cancer through a Nucleotidase Independent Mechanism. Issue 6 (23rd December 2022)

• Record Type: Journal Article
• Authors: Liu, Weishuai; Yu, Xiaozhou; Yuan, Yudong; Feng, Yixing; Wu, Chao; Huang, Chongbiao; Xie, Peng; Li, Shengnan; Li, Xiaofeng; Wang, Ziyang; Qi, Lisha; Chen, Yanan; Shi, Lei; Li, Mulin Jun; Huang, Zhiyong; Tang, Bo; Chang, Antao; Hao, Jihui
• Is Part Of: Advanced science. Volume 10:Issue 6(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-23
• Subjects: CD73 -- diclofenac -- epithelial‐mesenchymal‐transitions -- metastasis -- pancreatic ductal adenocarcinoma; Science -- Periodicals; 505
• DOI: 10.1002/advs.202206335
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: CD73, a cell surface‐bound nucleotidase, facilitates extracellular adenosine formation by hydrolyzing 5′‐AMP to adenosine. Several studies have shown that CD73 plays an essential role in immune escape, cell proliferation and tumor angiogenesis, making it an attractive target for cancer therapies. However, there are limited clinical benefits associated with the mainstream enzymatic inhibitors of CD73, suggesting that the mechanism underlying the role of CD73 in tumor progression is more complex than anticipated, and further investigation is necessary. In this study, CD73 is found to overexpress in the cytoplasm of pancreatic ductal adenocarcinoma (PDAC) cells and promotes metastasis in a nucleotidase‐independent manner, which cannot be restrained by the CD73 monoclonal antibodies or small‐molecule enzymatic inhibitors. Furthermore, CD73 promotes the metastasis of PDAC by binding to the E3 ligase TRIM21, competing with the Snail for its binding site. Additionally, a CD73 transcriptional inhibitor, diclofenac, a non‐steroidal anti‐inflammatory drug, is more effective than the CD73 blocking antibody for the treatment of PDAC metastasis. Diclofenac also enhances the therapeutic efficacy of gemcitabine in the spontaneous KPC (LSL‐Kras G12D/+, LSL‐Trp53 R172H/+, and Pdx‐1‐Cre) pancreatic cancer model. Therefore, diclofenac may be an effective anti‐CD73 therapy, when used alone or in combination with gemcitabine‐based chemotherapy regimen, for metastatic PDAC. Abstract : CD73 is overexpressed in the cytoplasm of pancreatic cancer cells and promotes metastasis in a nucleotidase‐independent manner. On this basis, a CD73 transcriptional inhibitor diclofenac is then developed, which is more effective than the CD73 blocking antibody for the treatment of metastasis. Moreover, diclofenac also enhances the therapeutic efficacy of gemcitabine both in mouse xenograft and spontaneous pancreatic cancer models.