Research Paper Volume 12, Issue 1 pp 611—627

Aspirin enhances the sensitivity of colon cancer cells to cisplatin by abrogating the binding of NF-κB to the COX-2 promoter

Wei Jiang 1, *, , Yue Yan 2, *, , Manyu Chen 1, *, , Guangyu Luo 2, *, , Jiaojiao Hao 1, , Jinjin Pan 1, , Sheng Hu 1, , Ping Guo 1, , Wenyang Li 1, , Ruozu Wang 1, , Yan Zuo 1, , Yao Sun 1, , Silei Sui 1, , Wendan Yu 1, , Zhe Pan 1, , Kun Zou 1, , Zongheng Zheng 3, , Wuguo Deng 2, , Xiaojun Wu 2, , Wei Guo 1, ,

  • 1 Institute of Cancer Stem Cells and The First Affiliated Hospital, Dalian Medical University, Dalian, China
  • 2 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
  • 3 The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
* Equal contribution

received: August 1, 2019 ; accepted: December 23, 2019 ; published: January 6, 2020 ;

https://doi.org/10.18632/aging.102644
How to Cite

Copyright © 2020 Jiang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Cisplatin is one of the most potent chemotherapeutic agents for the treatment of colon cancer. Nevertheless, the unavoidability of the notable toxicity and the development of the acquired resistance severely restricted its clinical application. Aspirin and some other non-steroidal anti-inflammatory drugs have been used to prevent colon tumorigenesis as chemopreventive agents. Here, we explored the possibility of aspirin as an adjuvant drug to boost the anti-cancer effect of cisplatin for colon cancer. We found that aspirin significantly enhanced the cisplatin-mediated inhibitions of cell proliferation, migration and invasion and the induction of apoptosis in colon cancer cells. The combined treatment of aspirin and cisplatin suppressed the expression of the anti-apoptotic protein Bcl-2 and the EMT-related proteins, up-regulated the levels of the cleaved PARP and Bax, and blocked the PI3K/AKT and RAF-MEK-ERK signaling pathway. In addition, we demonstrated that the enhanced effect of aspirin on the cisplatin-induced inhibition of tumor cell growth was also mediated through the suppression of the binding activity of NF-κB to the COX-2 promoter. The combination of aspirin and cisplatin effectively attenuated the translocation of NF-κB p65/p50 from the cytoplasm to the nucleus, and abrogated the binding of NF-κB p65/p50 to the COX-2 promoter, thereby down-regulating COX-2 expression and PGE2 synthesis. Moreover, the in vivo study also verified the enhanced anti-tumor activity of such combined therapy in colon cancer by targeting the NF-κB/COX-2 signaling. Our results provided new insights into understanding the molecular mechanisms of aspirin in sensitizing cisplatin-mediated chemotherapeutic effect in colon cancer and indicated a great potential of this combined therapy for cancer treatment.

Abbreviations

FBS: Fetal Bovine Serum; PGE2: Prostaglandin E2; IHC: Immunohistochemistry; FACS: Fluorescence Activated Cell Sorter; CB: Celecoxib; LPS: Lipopolysaccharides; DDP: Cisplatin; ASP: Aspirin.