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Cordycepin inhibits lipopolysaccharide-induced cell migration and invasion in human colorectal carcinoma HCT-116 cells through down-regulation of prostaglandin E2 receptor EP4

  • Jeong, Jin-Woo (Freshwater Bioresources Utilization Bureau, Nakdonggang National Institute of Biological Resources) ;
  • Park, Cheol (Department of Molecular Biology, College of Natural Sciences, Dongeui University) ;
  • Cha, Hee-Jae (Department of Parasitology and Genetics, Kosin University College of Medicine) ;
  • Hong, Su Hyun (Department of Biochemistry, Dong-Eui University College of Korean Medicine) ;
  • Park, Shin-Hyung (Department of Pathology, Dong-Eui University College of Korean Medicine) ;
  • Kim, Gi-Young (Department of Marine Life Sciences, Jeju National University) ;
  • Kim, Woo Jean (Department of Anatomy, Kosin University College of Medicine) ;
  • Kim, Cheol Hong (Department of Pediatrics, Sungkyunkwan University Samsung Changwon Hospital) ;
  • Song, Kyoung Seob (Department of Physiology, Kosin University College of Medicine) ;
  • Choi, Yung Hyun (Department of Biochemistry, Dong-Eui University College of Korean Medicine)
  • Received : 2018.05.28
  • Accepted : 2018.09.03
  • Published : 2018.10.31

Abstract

Prostaglandin $E_2$ ($PGE_2$), a major product of cyclooxygenase-2 (COX-2), plays an important role in the carcinogenesis of many solid tumors, including colorectal cancer. Because $PGE_2$ functions by signaling through $PGE_2$ receptors (EPs), which regulate tumor cell growth, invasion, and migration, there has been a growing amount of interest in the therapeutic potential of targeting EPs. In the present study, we investigated the role of EP4 on the effectiveness of cordycepin in inhibiting the migration and invasion of HCT116 human colorectal carcinoma cells. Our data indicate that cordycepin suppressed lipopolysaccharide (LPS)-enhanced cell migration and invasion through the inactivation of matrix metalloproteinase (MMP)-9 as well as the down-regulation of COX-2 expression and $PGE_2$ production. These events were shown to be associated with the inactivation of EP4 and activation of AMP-activated protein kinase (AMPK). Moreover, the EP4 antagonist AH23848 prevented LPS-induced MMP-9 expression and cell invasion in HCT116 cells. However, the AMPK inhibitor, compound C, as well as AMPK knockdown via siRNA, attenuated the cordycepin-induced inhibition of EP4 expression. Cordycepin treatment also reduced the activation of CREB. These findings indicate that cordycepin suppresses the migration and invasion of HCT116 cells through modulating EP4 expression and the AMPK-CREB signaling pathway. Therefore, cordycepin has the potential to serve as a potent anti-cancer agent in therapeutic strategies against colorectal cancer metastasis.

Keywords

AMPK;Cell migration/invasion;Cordycepin;CREB;EP4

Acknowledgement

Supported by : National Research Foundation of Korea (NRF)

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